Flexible medical container with selectively enlargeable compartments and method for making same

ABSTRACT

A flexible container is provided for the storage and administration of medical solutions. The container incorporates a transparent front sheet made from a planar layer of a polymer and an opposing rear sheet. The rear sheet is made from a planar laminate layer. The front and rear sheets are sealed together along a common peripheral edge to form a volume enclosure. The volume enclosure is constructed of materials having high oxygen and moisture barrier properties which allows the container thermoplastic to be stored for extended periods of time without degrading the contents. The volume enclosure is then inflated with a pressurized gas to permanently stretch the front and rear sheets outwardly and to thereby increase the volume capacity of the container. An alternative embodiment of the container incorporates multiple compartments, separated by peelable seals, for containing a diluent and a medicament. The seals are ruptured by manipulation of the container to thereby mix the contents together for delivery through standard IV arrangement to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of patent application Ser. No.09/247,997, filed on Feb. 10, 1999 now U.S. Pat. No. 6,468,377, which isa division of patent application Ser. No. 08/967,692, filed Nov. 12,1997, now U.S. Pat. No. 5,910,138, which is a continuation-in-part ofapplication Ser. No. 08/837,927, filed Apr. 11, 1997, now U.S. Pat. No.5,944,709, which is a CIP of application Ser. No. 08/647,583, filed May13, 1996, now abandoned. The present invention is also related toapplication Ser. No. 09/206,449, now U.S. Pat. No. 6,117,123. All ofthese applications are commonly owned by the Assignee of the presentinvention, the entire disclosures of which are expressly incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to flexible, sterile containers, forstoring and administering medical solutions in a sterile environment.More particularly, the present invention relates to flexible medicalcontainers for storing and administering IV solutions and having sideswhich are permanently stretched to enlarge their storage capacity.

BACKGROUND OF THE INVENTION

Various medical solutions are commonly administered intravenously (viaIV) from sterile containers to patients. These solutions may include anymedical type fluids, such as replacement body fluids and even solutionscontaining a medicament (drug). Common packaging for the storage andadministration of these solutions includes flexible containers having acompartment for storing the solution. An outlet port is coupled to thecompartment for administration and delivery of the solution to thepatient through a standard IV arrangement.

Oftentimes, medical solutions consist of a mixed combination of a liquiddiluent, e.g., an aqueous dextrose or NaCl solution, and a liquidmedicament. Desirably, the medicament and diluent are stored separatelyin the container under aseptic conditions and are not mixed togetheruntil immediately prior to use so as to prevent degradation of the finalproduct. Packaging of the diluent and medicament is often furthercomplicated by the character of the medicament which may be in liquidform and, thus, susceptible to hydraulic pressure on the container, aswell as degradation under light or oxygen exposure.

Accordingly, various such medicaments which become unstable with time insolution have typically been separately stored in gas-impermeable vials,containers, or the like prior to their use. Before being administered toa patient, medicaments stored in this fashion must be mixed, or dilutedin, a physiological solutions or diluents which are also preservedseparately. While able to maintain medicament sterility andeffectiveness, separate component storage is cumbersome and involves therisk of bacteriological contamination during handling, mixing, andsubsequent administration to a patient. Accordingly, medical containershave been developed which include compartments for storing unstablemedicaments and compartments which contain diluent liquids. Immediatelyprior to IV administration to a patient, the components are placed incommunication with one another so that the contents can be mixedtogether aseptically.

Multiple compartment containers, which allow separate storage ofdiluents and medicaments are known. Such containers are disclosed, forexample, in U.S. Pat. No. 4,608,043 to Larkin, U.S. Pat. No. 5,176,634to Smith et al. and U.S. Pat. No. 5,462,526 to Barney et al. U.S. Pat.Nos. 4,608,043, 5,176,634 and 5,462,526 are expressly incorporatedherein in their entirety by reference. The compartments of thecontainers disclosed in the foregoing patents are separated from oneanother by peelable or frangible heat seals. The seals are ruptured bymanipulation of the container so that the contents of the compartmentscan be mixed together to thereby form a solution which is delivered tothe patient through a standard IV arrangement.

Solution containers on the market today are generally manufactured ofmaterials comprising PVC plastic. PVC material is generally quite murkyin aspect, making it difficult to inspect the contents of a containermanufactured of such material. Consequently, inspecting such containersfor leaks and moisture contamination is quite difficult. Inspection iffurther complicated when using multiple compartment containers, wherethere is a need to verify whether complete mixing of the medicament anddiluent has taken place prior to administration to a patient. Inaddition, various hazardous chemicals are used in the manufacture of PVCmaterial which must be disposed of in an environmentally safe manner.PVC containers must be carefully disposed of following their use,because PVC emits a toxic gas when incinerated and includes a toxicplasticizer that can leach into the surrounding environment if thecontainer is buried in a landfill. This toxic plasticizer is also ableto leach into IV solutions, making PVC containers unsuitable for usewith several types of medical fluids, and particularly with liquiddrugs.

These flexible containers are typically fabricated from a pair ofopposing planar sheets which are mated together to form a body or shell.Forming a particular sized body results in a fixed volume capacity.Typically, the containers are fabricated to hold standardized volumes.This works well until a non standard volume is necessary. In thissituation, one option is to utilize only a portion of the solutionstored in a larger container. However, this option is expensive,wasteful and dangerous. The user must also be very careful to only usedthe desired quantity or prescription of the contained fluid. Inaddition, any remaining solution may require specialized disposal.

The containers are also typically fabricated to a predetermined overallouter size or a few common overall sizes. This is generally because theoverall size of the container determines its volume capacity, andcurrently containers are provided in a relatively few predeterminedvolumes. In addition, the fabrication, handling and sterilization ofthese containers requires highly complex and expensive machinery. Thismachinery is designed, in part, to handle the overall dimensions of thecontainer. It is therefore desirable to provide a medical containerwhich has a standard overall outer size and has an enlarged volumecapacity relative to the standard size. It is further desirable that themedical container be fabricated using the same machinery and handlingequipment as that for standard size containers.

Similar to the single compartment containers, multi-compartmentcontainers are typically constructed with predetermined compartmentsizes. The diluent compartment is typically sized to hold a sufficientquantity of diluent to mix with the stored medicament and form a propersolution. The diluent compartment size is also based on a particulardosage or stored quantity of the medical solution. The volume of thediluent compartment may also be limited by the overall outer size of thecontainer which must be constructed to fit the packaging and handlingequipment. However, in some applications, it may be desirable toincrease the quantity of diluent. Currently this is not possible orrequires a second container of diluent. Alternatively, some applicationsmay require additional medicament. It is therefore desirable to providea multi-compartment medical container that has a standard overall outersize with standardized compartment volume capacities that can bepermanently enlarged to increase the volume capacity of at least one ofthe compartments. It is further desirable that the container bemanufactured to a predetermined overall size and configuration tofacilitate manufacturing, sterilization and handling by the samemachinery and processes

SUMMARY OF THE INVENTION

The present invention provides a flexible medical container for storingmedical solutions which is capable of being permanently enlarged toincrease its storage capacity. The present invention also provides aflexible medical container for storing medical solutions and powderswhich is manufactured to a standardized overall size and optionallyenlarged to increase its storage capacity. By providing a flexiblecontainer having a front sheet and a rear sheet which can be permanentlystretched, the volume capacity of the container can be increased to avariety of sizes and shapes. By adding a simple, optional, enlargingstep to the container manufacturing process, the volume enclosure ofsome containers may be enlarged while others may be kept at a generallystandardized or non-enlarged capacity. This advantageously allows thepresent containers to be substantially fabricated, handled andadministered using current methods and equipment.

In one aspect of the present invention, a flexible container forcombined storage and administration of a medical fluid is provided. Theflexible container includes a substantially transparent front sheethaving a first surface area. The front sheet is constructed from aflexible planar layer of a polymer film. A rear sheet having a secondsurface area and being constructed from a flexible planar layer of alaminate is disposed opposing the front sheet. The front sheet and therear sheet are sealably attached together along a common peripheral edgeto form a volume enclosure. A port is supported along the commonperipheral edge and fluidly connected with the volume enclosure. Atleast one of the front sheet and the rear sheet is permanently elongatedto increase the storage capacity of the volume enclosure and thus, thecontainer.

In another aspect of the present invention, the flexible containerincludes a substantially transparent front sheet having a first surfacearea. The front sheet is constructed from a flexible planar layer of apolypropylene-polyethylene copolymer blended with a styreneethylene-butylene styrene thermoplastic elastomer. A similarly sizedrear sheet having a second surface area is disposed opposing the frontsheet. The rear sheet is constructed from a flexible planar layer of alaminate including an inner layer of a polypropylene-polyethylenecopolymer blended with a styrene ethylene-butylene styrene thermoplasticelastomer. This inner layer is disposed facing the opposing front sheet.The rear sheet also includes an intermediate layer of an aluminum foiland an outer thermoplastic layer having a higher melting point than theinner layer. The front sheet and the rear sheet are sealably attachedtogether along a portion of the common portion of the peripheral edge toform a volume enclosure.

A first peelable seal extends between a first side of the commonperipheral edge and an opposing second side of the common peripheraledge. This first peelable seal joins the front sheet and the rear sheettogether to form a first compartment within the volume enclosure forcontaining a diluent. A second peelable seal extends between theopposing first and second sides of the common peripheral edge. Thissecond peelable seal joins the front sheet and the rear sheet togetherto form a second compartment for containing a medicament and a thirdoutlet compartment. The second compartment is disposed between the firstcompartment and the outlet compartment.

An outlet port is supported along the common peripheral edge. The outletport is fluidly connected to the outlet compartment. A diluent port isalso supported along the common peripheral edge. The diluent port isfluidly connected with the first compartment through a break in the sealalong the common peripheral edge. A medicament port is also supportedalong the common peripheral edge. A medicament port is fluidly connectedwith the second compartment through a second break in the seal along thecommon peripheral edge.

In yet a further aspect of the present invention, a method for forming aflexible container for combined storage and administration ofmedicaments and diluents for IV solutions is disclosed. The methodincludes the steps of providing a substantially transparent front sheetand a flexible and vapor impermeable rear sheet. The provided frontsheet is constructed from a flexible planar layer of a polymer film. Therear sheet is constructed from a planar multi layer laminate. The frontsheet and the rear sheet are sealed together along their commonperipheral edge so as to define a volume enclosure.

The method also includes the steps of providing first and secondsacrificial ports which are supported along a first side of the commonperipheral edge and fluidly connected to the volume enclosure. The firstsacrificial port is spaced apart from the second sacrificial port alongthis first side. The outlet port is supported along a second side of thecommon peripheral edge and is also fluidly connected to the volumeenclosure.

The volume enclosure is expanded through inflation with a pressurizedgas to permanently stretch at least the front sheet and to therebyincrease the volume capacity of the container. The pressurized gas isthen relieved from the expanded container. The permanently stretchedvolume enclosure is then filled with a second gas. The sacrificial portsand the outlet port are then capped to maintain the container in anexpanded configuration.

After the container has been permanently expanded, each of thesacrificial ports may be removed. This step includes removing a portionof the first side along the common peripheral edge. The front sheet isthen sealably attached to the rear sheet along the first side inwardlyfrom the sacrificial ports to form a continuous permanent seal about thecommon peripheral edge.

In yet a further aspect of the present invention, a method forincreasing the capacity of a flexible container for storage andadministration of medical fluids is disclosed. The method includesproviding a flexible container, such as the container of the presentinvention. The provided container includes a flexible planar front sheetopposing a flexible planar rear sheet along a common plane. The frontsheet is sealably attached to the flexible rear sheet along a commonperipheral edge to form a volume enclosure. A port is connected to thecontainer and fluidly connected with the volume enclosure. The methodincludes the step of expanding the volume enclosure to permanentlystretch at least the front sheet and thereby increase the volumecapacity of the container.

The step of expanding the volume enclosure includes providing amulti-piece tool which is configured for receiving the volume enclosure.The tool includes a lower tool portion and an opposing upper toolportion. The lower tool portion has a lower planar edge surrounding alower concave region. In a similar configuration, the upper tool portionhas an upper concave region with surrounding upper planar edge. Thelower and upper planar edges are generally opposed and configured tocapture the common peripheral edge. The container is sandwiched betweenthe tool such portions with rear sheet facing the lower concave regionand the front sheet facing the upper concave region. The volumeenclosure is then inflated with a pressurized gas to permanently stretchthe front and rear sheets outwardly and against the respective concaveregions of the tool. The volume enclosure is maintained inflated for atime sufficient to overcome substantial elastic rebounding.

In yet a further aspect of the present invention, a second method forforming a flexible container for combined storage and administration ofmedicaments and diluents for IV solutions is disclosed. The methodincludes providing a flexible and substantially transparent front sheetconstructed from a planar layer of a polymer. A flexible and vaporimpermeable rear sheet constructed from a planar multi-layer laminate isalso provided. The front sheet and the rear sheet are sealed togetheralong a portion of a common peripheral edge to define a volumeenclosure. The front sheet and the rear sheets are heated in a firstlocalized area to fuse them together along the heated first localizedarea and thereby form a first peelable seal. This first seal extendsbetween a first side of the common peripheral edge and an opposingsecond side of the peripheral edge. The first seal separably joins thefront sheet to the rear sheet and thereby forms a first compartmentwithin the volume enclosure for containing a diluent. The front and rearsheets are also heated along a second localized area to form a secondpeelable seal. The second peelable seal extends between the first sideand the opposing second side of the common peripheral edge and separablyjoins the front and rear sheets together to thereby form a secondcompartment for containing a medicament. The second compartment isdisposed between the first compartment and the outlet compartment.

The method also includes providing a first sacrificial port interposedbetween the front and rear sheets and in communication with the firstcompartment. A second sacrificial port is also interposed between thefront and rear sheets. However, the second sacrificial port is spacedapart from the first sacrificial port and is fluidly connected with thesecond compartment. An outlet port is also interposed between the frontand rear sheets. The outlet port is fluidly connected with the outletcompartment. The portion of the volume enclosure forming the firstcompartment is then expanded to permanently stretch the front sheet andthe rear sheet and to thereby increase the volume capacity of the firstcompartment.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects and advantages of the presentinvention will be more fully understood when considered with regard tothe following detailed description, appended claims and accompanyingdrawings wherein:

FIG. 1 is a semi-schematic front view of an exemplary embodiment of acontainer provided in accordance with the principles of the presentinvention;

FIG. 2 is a semi-schematic side cross-sectional view taken along theline 2—2 of FIG. 1, depicting the flexible planar sheets formed in thecontainer, with the thickness of the layers in the sheets exaggeratedfor clarity;

FIG. 3 is a semi-schematic fragmentary cross-sectional view taken alongthe line 3—3 of FIG. 2, showing the configuration of the flexible sheetsof a first embodiment of the container of the present invention;

FIG. 4 is a semi-schematic fragmentary cross-sectional view of theconfiguration of the flexible sheets of a first embodiment of theinvention depicting an optional, transparent, high-barrier intermediatefilm;

FIG. 5 is a semi-schematic side cross-sectional view taken along theline 2—2 of FIG. 1, depicting a permanently enlarged first compartmentrelative to FIG. 2;

FIG. 6 is a semi-schematic front view of an exemplary embodiment of thecontainer shown during fabrication in accordance with the principles ofthe present invention;

FIG. 7 is a diagrammatic plan view of an embodiment of a modularcontainer fabrication apparatus in accordance with the presentinvention;

FIG. 8 is an alternative embodiment of a flexible container according tothe principles of the present invention;

FIG. 9 is a side elevational view of the flexible container of FIG. 8;

FIG. 10 is a side elevational view of the flexible container of FIG. 8shown with the front and rear sheets permanently enlarged;

FIG. 11 is a perspective view of an embodiment of a tool for permanentlystretching the front and rear sheets of the flexible container accordingto the principles of the present invention;

FIG. 12 is a perspective view of an upper portion of the tool of FIG.11, showing the upper cavity;

FIG. 13 is a perspective view of an embodiment of an actuator housingfor use with the tool of FIG. 11;

FIG. 14 is a semi-schematic perspective view of a handling containerprovided in accordance with the principles of the present invention,including a rail cartridge and a sealable film lid;

FIG. 15 is a semi-schematic plan view of the rail cartridge of FIG. 14,showing a plurality of flexible containers loaded into the rails;

FIG. 16 is a semi-schematic side elevational view of the loaded railcartridge of FIG. 15 showing how the flexible containers are held withinthe rails by the sacrificial ports; and

FIG. 17 is a side elevational view of the flexible container of FIG. 8shown with the sacrificial ports removed and the permanent sealcompleted along the entire common peripheral edge.

DETAILED DESCRIPTION

Referring to FIGS. 1 and 2, there is shown schematic front andcross-sectional side views, respectively, of a preferred embodiment of aflexible, sterile container 10 provided in accordance with practice ofprinciples of the present invention. Although the container 10 can beviewed in any orientation, for purposes of explanation, the position ofthe compartments of the container relative to one another are describedwith reference to the orientation of FIGS. 1 and 2. The container 10 isformed from a generally planar front sheet 12 and an opposing generallyplanar back or rear sheet 14 (shown only in FIG. 2). The front and rearsheets 12 and 14 may be constructed of a single layer of flexiblematerial or multi-layer laminates of flexible material which will bedescribed in greater detail below.

The sheets 12 and 14 forming the container 10 may be provided separatelyand disposed opposing each other along a common plane 15 (FIG. 2). Thesheets 12 and 14 are then sealed together along a common peripheral edge16 with a permanent seal. Preferably, the sealed common peripheral edge16 extends around the entire periphery of the container 10 to form avolume enclosure 17. Such peripheral seals may vary in configuration andwidth. A patterned seal, such as that depicted on the top or upper side18 and the bottom or lower side 20 of FIG. 1, may be used to definegrasping areas which allow clinical personnel to handle the container 10and allow for the container to be attached to, for example, an IVsupport stand. Alternatively, the front and rear sheets 12 and 14 may beformed from a single film sheet which is subsequently folded-over andsealed together by means of the heat seal which extends around theperiphery of the lapped-together portions of the film sheet. Howeverformed, the sealed-together sheets shall be referred to herein as the“shell” or “body” of the container.

In the exemplary embodiment, the container 10 is partitioned into threeseparate compartments; a first or upper compartment 22, a second orintermediate compartment 23 and a lower or outlet compartment 24, eachof which is sterile. The upper and intermediate compartments 22 and 23are separated from one another by a first peelable seal 25, while theintermediate and lower compartments 23 and 24 are separated from oneanother by a second peelable seal 26. The peelable seals 25 and 26extend between a first side 27 of the container 10 and an opposingsecond side 28. The peelable seals 25 and 26 span from the sealed commonperipheral edge 16 on the first side 27 to the sealed common peripheraledge 16 on the second side 28. The peelable seals 25 and 26 join theinterior faces of the front and rear sheets 12 and 14 together in thelocalized area or region of the seals.

A “peelable” seal, as the term is used herein, is a seal which issufficiently durable to allow normal handling of the container yet whichwill peel-open, allowing separation of the front sheet from the backsheet in the region of the seal, under hydraulic pressure applied bymanipulating the container, thereby allowing mixing and dispensing ofthe container contents. A peelable seal is formed by partially meltingtogether the polymeric material present in the adjoining interior facesof the front and back sheets. The seal is obtained by a heat sealingprocess by which heat and pressure is applied to a localized area withvarying times, temperatures, and pressures which will be described ingreater detail below. Conversely, the seal along the common peripheraledge 16 is significantly stronger than the “peelable” seals 25 and 26and will not be ruptured by the hydraulic pressures generated toseparate the peelable seals. Each of the peelable seals, 25 and 26, areindividually configured so as to peel-open in a manner thatpreferentially allows liquid medicament and liquid diluent to mix first,and then allow the mixed components to be dispensed.

In a typical application for the container 10 of the present invention,the upper compartment 22 is filled with a liquid diluent in theintermediate compartment 23 is filled with a medicament, typicallyprovided in liquid form. The lower compartment 24 functions as asecurity interface for an outlet port 30 and remains empty until thecontainer is used. The outlet port 30 extends downwardly and comprises abody portion 38 and a nozzle 40 which is configured for attachment to astandard IV administration device. A cap (not shown) is provided tocover the nozzle and maintain its sterility. The cap is removed justprior to attachment of an IV set to the outlet port 30. A plurality ofribs 39 may provided in spaced-apart relationship about the body portion38 of the outlet port 30 to provide an easily grasped surface and tofacilitate attachment with an IV set.

The materials employed in constructing the front and rear sheets of thecontainer 10 are selected based on the material to be stored therein.Preferably, at least one of the sheets is transparent to allow thecontents of the container to be visually inspected and to allow thelevel of the solution in the container to be visually verified duringdispensing. Suitable materials for the fabrication of the transparentsheet are typically single-layer and multi-layer laminated polymers andpolymer films.

In particular, whether constructed of a single-layer or a multi-layerlaminated polymer film, the materials comprising the front 12 and rear14 sheets of the container 10 are chosen for their clarity andtransparency. Conventional polyvinyl chloride (PVC) container materialsare generally quite murky in appearance, making it difficult toadequately view the interior of the container and determine the levelsof any fluids contained therein or the presence of particulate matter.This is a particularly dangerous situation when administering medicationintravenously. It is imperative that a nurse or clinical worker be ableto tell, at a glance, that any such medication being administered from amedical container is free from particulate matter.

Referring now to FIG. 3, a fragmentary schematic cross-section of anembodiment of the container 10 is shown. As depicted, the front sheet 12is constructed of a transparent, single-layer thermoplastic polymer film44. The transparent film 44 may be fabricated from a planer layer orsheet comprising a blend of about 80% by weightpolypropylene-polyethylene copolymer available from Fina Oil andChemical Company of Deerpark, Tex., having a commercial designation ofZ9450, and about 20% by weight styrene ethylene-butylene styrenethermoplastic elastomer, available from Shell Chemical Corporation underthe trade name KRATON® and having a commercial designation G1652. G1652thermoplastic elastomer is a two-phase polymer with polystyrene domains(end blocks) in a rubbery poly (ethylene-butylene) matrix and istypically provided in crumb form. In practice, the film is made bymixing pellets of the Z9450 co-polymer resin and G1652 thermoplasticelastomer, in crumb form, in an 80%/20% by weight ratio, in a high shearmixer and melting and repelletizing the mixture. Compounding the G1652crumb in high shear equipment can cause the temperature to rise, so careshould be taken so that the temperature is not allowed to exceed about500° F. Subsequently, the transparent film 44 is formed from the blendedpellets in a commercial extrusion apparatus.

The transparent polymer film 44 comprising the front sheet 12 may beconstructed with varying thicknesses, depending on the use to which thecontainer is put and the durability required for that particularapplication. Suitable thicknesses for the material comprising the frontsheet 12 may range from about 3 to about 15 mils, but in the illustratedcontainer embodiment, the transparent polymer film 44 comprising thefront sheet 12 is preferably about 12 mils thick.

Although the composite material chosen for forming the transparentpolymer film 44 (which may be referred alternatively as the “80:20film”) were chosen based on their clarity and transparency, the film 44is also particularly suitable for forming both “peelable” seals andpermanent seals, such as the permanent seal along the common peripheraledge 16 of the container 10. As will be described in greater detailbelow, the 80:20 film, in accordance with the invention, is able toaccommodate both lower-temperature peelable seal and higher-temperaturepermanent seal formation processes without effecting the material'sintegrity or its ability to provide an effective peelable or permanentseal.

For certain medical solutions, including certain combinations ofdiluents and medicaments, the rear sheet 14 can be formed with the samesingle layer composition and configuration as the front sheet 12.Alternatively, multi-layer films, which include layers that areimpermeable to moisture and light and are able thereby to extend theshelf life of a filled container, are preferred films for constructionof the rear sheet. As illustrated, a three-layer laminate rear sheet 14may be employed. Preferably, the laminate rear sheet 14 is a flexibleplanar sheet that is impermeable to water vapor and light. Thisconfiguration preserve the effectiveness and activity of the solution inthe single compartment container 10 and the binary components (theunmixed medicament and diluent liquids) with multi-compartmentcontainers and thus, increases the shelf life of the filled container.

In the exemplary embodiment illustrated, the rear sheet 14 includes aninner sealing or seal layer 46 on its inwardly facing surface. Thisinner seal layer 46 may be constructed of an 80%/20% wt/wt blend ofpolypropylene-polyethylene copolymer and styrene ethylene-butylenestyrene thermoplastic elastomer the blend having a thickness of about 3to 6 mils (the 80:20 film). Preferably, the inner seal layer 46 (the80:20 film layer) may be approximately 6 mil. thick, which is bonded bymeans of a transparent inner adhesive 48 to an intermediate layer 50.Preferably, this intermediate layer 50 may be an approximately 0.7 milto 1.3 mil, and more preferably about 1.0 mil, high-barrier aluminumfoil layer. An outer layer 54 is provided on the outwardly facingsurface of the rear sheet 14 and is bonded to the high-barrier aluminumfoil layer 50 by means of a suitable transparent adhesive 52.

The inner adhesive layer 48 may comprise a modified aliphatic polyesterpolyurethane adhesive, available from Liofol Company of Cary, N.C.,under the commercial designation TYCEL 7909. The outer adhesive layer 52may comprise a modified aromatic polyester polyurethane adhesive, alsoavailable from Liofol Company of Cary, N.C., under the commercialdesignation TYCEL 7900. The aliphatic adhesive comprising the inneradhesive layer 48 may also be used for the outer adhesive layer 52,although the converse is not the case. The aromatic adhesive, whileproviding a stronger bond than the aliphatic version, has the potentialfor introducing extremely undesirable aromatic compounds into either theliquid diluent or liquid medicament, through the 80:20 film layer.Accordingly, the aromatic adhesive, when used, is only used when thealuminum foil layer 50 is interposed as a barrier between it and thevolume container 17 within the container 10.

The aluminum foil layer 50 is suitably constructed of a commerciallyavailable 1.0 mil aluminum foil, such as ALCAN 1145, available from theAlcan Rolled Products Company, of Louisville, Ky. When the aluminum foillayer 50 remains exposed as the exterior layer of the rear sheet 14, theheat sealing process, used to form both the seal along the commonperipheral edge 16 and the transverse peelable seals 25 and 26 maydamage the foil layer 50 and degrade its integrity and ability toprovide a barrier. The outer high temperature layer 54 is provided toprevent this damage. Preferably, the outer layer 54 is constructed of arelatively high-melting polymer which functions as a protective layerover the aluminum film and prevents contact between the intermediatefoil layer 50 and the hot platens of a heat seal apparatus. Further, thehigh-temperature layer 54 functions as a heat seal release (also termedmold release) layer because the material does not melt and stick to theheat seal platens at the temperatures used during the seal formationprocesses. Pressure and temperature can thus be applied to the exteriorof the container without the need for special coatings on the platens.Preferably, the outer layer 54 may have a higher melting temperaturethan the inner seal layer 46.

The outer high-temperature layer 54 is preferably a polyethyleneterephthalate (designated herein as PET) available from Rhone-Poulancunder the commercial designation TERPHANE 10.21, having a thickness inthe range of from about 0.4 to about 0.06 mils. In the illustratedembodiment, the thickness dimensions of the components of themulti-layer laminate film 14 are preferably about 0.48 mils for theouter, high-temperature polyester layer 54, about 1.0 mils for thehigh-barrier aluminum foil layer 50, and about 6.0 mils for the 80:20inner seal layer film 46.

It has been found that preferable material choices for the front andrear sheets 12 and 14, which result in optimum performance of thepeelable seals 25 and 26, incorporate an interfacing seal layer on eachsheet comprising the 80:20 film. Alternatively, the inner facing seallayers of the front and rear sheets may comprisepolypropylene-polyethylene co-polymer and styrene ethylene-butylenestyrene thermoplastic elastomer blends having differing relativepercentages. The relative percentages used will depend on thecharacteristics of the various seals contemplated for use in connectionwith a particular medical container, and the temperature and pressureparameters of the seal formation processes. Other types of flexiblefilms which may be useful in the construction of the front and rearsheets of the shell of the container 10 of the present invention, aswell as the inner facing seal layers on both sheets, are disclosed inU.S. Pat. Nos. 4,803,102, 4,910,085, 5,176,634 and 5,462,526, the entiredisclosures of which are expressly incorporated herein by reference.

In certain applications, particularly with multi-compartment containers,such as the container illustrated in FIGS. 1-2, additional protectionmay be desirable. This may be especially true where the medicament issusceptible to contamination by water vapor or degradation caused byradiation in the visible or UV portion of the spectrum and thus,requires additional protection over the portion of the front sheet 12covering the intermediate (medicament) compartment 23. However, thisadditional protection may be provided over any number of compartments oreven over the entire front sheet 12. The additional protection may beprovided to preclude moisture, oxygen, and/or light transmission throughthe portion of the front sheet 12 comprising the second or intermediatecompartment 23 and to protect the medicament from degradation. Suchadditional protection allows the container 10 to be stored forsubstantial periods of time without loosing medicinal efficacy.

Referring in particular to FIGS. 2 and 3, an opaque film 55 havinghigh-barrier properties, is employed to cover the intermediatecompartment 23. The opaque film 55 interposes a barrier to moisturevapor and free oxygen permeation into the medicament compartment and, inthe exemplary embodiment, comprises a multi-layer laminate structurewhich includes a high-barrier aluminum foil layer. The use of an opaquealuminum foil laminate helps prevent the medicament contained in theintermediate compartment 23 from being degraded due to exposure toinvisible light and UV radiation. Thus, in the illustrated embodiment,the opaque aluminum foil comprising both a protective film 55 and therear sheet 14 encloses the intermediate compartment 23 and preventspenetration of UV invisible spectrum light into the intermediatecompartment 23 from either direction.

The high-barrier protective film 55 may be a multi-layer laminate,constructed of an inner seal layer 56 on its inwardly facing surface. Inthe exemplary embodiment, the seal layer 56 is a soft co-extrusioncoated resin comprising a modified ethylenevinylacetate polymeravailable from the Dupont Chemical Company under the commercialdesignation APPEEL 1181, provided in a thickness of from about 0.2 toabout 0.4 mils. An aluminum foil layer, such as ALCAN 1145, from about0.7 to about 1.3, and preferably about 1.0, mils thickness is bonded tothe inner seal layer 56 by means of a suitable transparent adhesive 57.An outer, heat seal release layer 60 comprising apolyethyleneterephthalate (PET) film, such as TERPHANE 10.21,approximately 0.48 mils in thickness, forms the outwardly facing surfaceof the high-barrier protective film 55. The heat seal release layer 60is bonded over the aluminum foil layer 58 by means of a suitabletransparent adhesive 59. The adhesive layers 57 and 59, of the presentembodiment, suitably comprise a modified aliphatic polyesterpolyurethane adhesive available from Liofol Company under the commercialdesignation TYCEL 7909. Alternatively, the outer transparent adhesive 59may comprise a modified aromatic polyester polyurethane adhesive, alsoavailable from Liofol Company, under the commercial designation TYCEL7900. Because of the dangers attendant with aromatic compounds leachinginto either the liquid diluent or liquid medicament, the aromaticadhesive is only used on the outside of the aluminum foil layer 58. Theinner adhesive layer 57 will preferably comprise an aliphatic adhesive.

Because the inner seal layer 56 of the high-barrier protective film 55may be a co-extrusion coated resin, it is able to form a peelable seal,over a broad temperature range, when applied to a number of differentmaterials. Materials to which such a co-extrusion coated resin may forma peelable seal include acrylonitrile-butadiene-styrene (ABS), highdensity polyethylene (HDPE), high impact polystyrene (HIPS),polypropylene (PP), polystyrene (PS), polyvinylchloride (PVC), and the80:20 film which comprises the front sheet 12 of the container. Thehigh-barrier protective film 55 may thus be removably (peelably orseparably) affixed to the outer surface of the front sheet 12 coveringthe intermediate or the medicament compartment 23.

Preferably, the high-barrier protective film 55 is removable (peelableor separable) from the container 10 prior to its use, to allow visualexamination of the state of the medicament in the medicament compartment23. In the exemplary embodiment, best seen in connection with FIG. 1, aprotective film 55 includes an extending tab 62 which may be grasped inorder to peel the protective film 55 away from the transparent frontsheet 12. The contents of the medicament compartment 23 are therebyexposed for easy visual inspection.

The high-barrier protective film 55 may be sealed and adhered to only aportion of the front sheet 12. Preferably, those portions of thehigh-barrier protective film 55 which are not sealed to the underlyingmaterial of the front sheet 12 define a regular array or pattern ofgenerally circular raised dimples 51 which are the tactile residue of aheat seal bar into which a rectangular array of holes has been cut. Whenthe heat seal bar is pressed over the surface of the high-barrierprotective film 55, a heat seal is provided only on the surface contactregions of the heat seal bar and not in the regions where the barmaterial has been removed (the holes). Since pressure is also appliedduring the process along with heat, the high-barrier protective film 55takes a reverse impression from the heat seal head, thus giving rise tothe textured, raised dimpled surface. The dimples 51 allow thehigh-barrier protective film 55 to be adequately sealed to theunderlying material (the front sheet) of the medical container but, atthe same time, provides for easy removal of the film 55 withoutapplication of undue force.

If the entire protective layer 55 was heat sealed onto the front sheet12, a relatively strong bond would be created and a larger than desiredamount of force would be required to completely peel it away. Byreducing the adhered surface area of the seal, a smaller force(proportional to the seal area) is required to remove the peelableopaque barrier. It is apparent from the foregoing description, that theamount of force required to remove the peelable aluminum strip isinversely proportional to the number of dimples (51 of FIG. 1) formed inthe film 55. Depending on the use to which the medical container is put,a more or less easily removable high-barrier protective layer may beeasily constructed by merely increasing or decreasing the number ofdimples formed in the layer during the heat seal process. It should benoted, however, that the high-barrier film 55 has its entire periphery,with the exception of the tab 62, heat-sealed to the underlying materialof the container. Forming a full peripheral seal around the high-barrierfilm 55 ensures that the film's barrier properties fully extend acrossthe medicament compartment 23.

In practical use, the filled container 10 may stored for a period oftime against eventual need. Typically, prior to dispensing, a pharmacistor other user removes the high-barrier foil layer 55 from the frontsheet 12 of the container 10 in order to visually check the integrity ofthe contents. If the container 10 is not put into use at that time, itis returned to storage and dispensed again at the next request. Removalof the peelable high-barrier film 55 leaves the contents of thecontainer, or particularly, of the medicaments in the intermediatecompartment 23 susceptible to degradation by moisture, light andpermeable oxygen. It is desirable that filled containers 10 inaccordance with the present invention are able to be stored for periodsof up to 30 days prior to use without the medical solution or medicamentbeing severely degraded by exposure to moisture and free oxygen afterthe high-barrier protective film has been removed from the medicamentcompartment.

Accordingly, and as illustrated in FIG. 4, a transparent high-barrierintermediate laminate film 64 is optionally interposed between thehigh-barrier aluminum foil-containing protective film 55 and the 80:20material of the container front sheet 12. Preferably, this intermediatelaminate film 64 is disposed over the portion of the front sheet 12covering the intermediate compartment 23. In this configuration, thetransparent high-barrier intermediate film 64 covers and protects thecontents of the intermediate compartment 23 after the peelablehigh-barrier protective film 55 is removed from the container 10. Thetransparent high-barrier intermediate film 64 exhibits barrierproperties which protects medical solutions and medicaments from atleast moisture vapor and oxygen permeation for a substantial periodwhich, depending on the specific activity of the medicament, may be aslong as 30 days. In other words, the opaque high-barrier protective film55 in combination with the transparent high-barrier intermediate film 64may be used to form a high-barrier protective covering over theintermediate compartment 23.

Pertinent to the characterization of the protective covering as a “high”barrier covering is the degree to which the protective covering isimpermeable to various penetrant gasses. Polymers are categorized by thedegree to which they restrict passage of penetrant gasses, e.g., oxygenor moisture vapor. The categories range from “high” barrier (lowpermeability) to “low” barrier (high permeability). The category inwhich a polymer is classified may vary according to the penetrant gas.As used herein, the term “high”-barrier, when it refers to moisturevapor permeability, means a film of a permeability of less than about1.5 g/mil/m²/24 hr/atm, at 30° C., 100% R.H. As used herein, the term“high”-barrier when it refers to oxygen permeability, means a film witha permeability of less than about 50 cc/mil/m²/24 hr/atm, at 25° C.,100% R.H.

The transparent high-barrier intermediate film 64 may include a triplelayer high-barrier laminate structure which is significantly resistantto free oxygen and water vapor permeability so as to protect thecontents of the medicament compartment and increase the shelf life of abinary container. In the illustrated embodiment, the intermediatelaminate film layer 64 includes an outer layer 66 of silica depositedpolyethyleneterephthalate (also termed SiO_(x) coated polyester orSiO_(x) coated PET) available from Mitsubishi Kasei under the commercialdesignation TECH BARRIER H. The sealant layer 56 of the high-barrierprotective film 55 is placed in contact with the outer layer 66 of theintermediate laminate film 64. An intermediate layer 68 comprising asilica deposited (SiO_(x) coated) polyvinylalcohol (PVA) film availablefrom Mitsubishi Kasei under the commercial designation TECH BARRIER S isbonded to the outer layer 66. On its inward facing surface, thetransparent high-barrier intermediate film 64 suitably comprises aninner seal layer 69 formed of a polypropylene-polyethylene copolymer.The copolymer may be blended with styrene ethylene-butylene styrenethermoplastic elastomer in various proportions, but a 100%polypropylene-polyethylene copolymer layer is preferred. The individuallayers of the intermediate laminate film 64 are adhesively bonded to oneanother. For clarity, these adhesive layers are not shown in the figurebut comprise a modified aliphatic polyester polyurethane laminateavailable from Liofol Company under the commercial designation TYCEL7909. The inner seal layer 69 is securely affixed to the outer surfaceof the front sheet 12 by an appropriate permanent heat or ultrasonicseal, an adhesive pressure seal, or the like. The transparenthigh-barrier intermediate laminate film 64 is sized, horizontally andvertically, to cover the entire surface area of the medicamentcompartment and also extends to cover the peelable and permanent sealsformed adjacent the medicament compartment.

Similar to the flexible, thermoplastic materials which comprise thefront sheet 12, the three-layer laminate structure of the intermediatelayer 64 is substantially optically clear and transparent to allowinspection of the contents of the medicament compartment 23. Thus,unlike polyvinyl chloride (PVC), and other similar materials, which arefairly hazy (translucent), the intermediate layer 64 of the presentinvention is visually transparent while imparting considerableprotection against moisture and free oxygen degradation.

In particular, the barrier properties of the transparent, high-barrierintermediate laminate film 64 are substantially greater than those ofconventional films, such as low-density polyethylene (LDPE),medium-density polyethylene (MDPE), linear low-density polyethylene(LLDPE), ethylene-vinylacetate copolymers (EVA), or blends of thesepolymers, in areas important to the functioning of the container, e.gmoisture and oxygen permeability. The oxygen permeability of theintermediate layer 64 is approximately 10 cc/mil/m²/24 hr/atm.Conversely, the oxygen permeability of EVA copolymers, LDPE and MDPE,respectively, are approximately 2500 (EVA 5%), 8300 (LDPE), and 8500(MDPE) cc/mil/m²/24 hr/atm. The oxygen permeability of LLDPE isapproximately the same or slightly higher than LDPE. Thus, the oxygenpermeability of the transparent high-barrier intermediate layer 64 isorders of magnitude less than the oxygen permeability of polymerstypically used to construct binary medical containers. In other words,the barrier properties of the high-barrier intermediate layer 64 areimproved by several orders of magnitude over the barrier properties ofpolymers typically used to construct these containers.

Because of the intermediate laminate film's barrier properties, thepeelable aluminum foil-containing protective film 55 may be removed by apharmacist in order to perform visual inspection of the container'scontents prior to dispensing, and the container may then be stored for areasonable additional period of time without the danger of oxygen ormoisture induced medicament degradation. Once the protective foil layeris removed, it is desirable that the container have a storage shelf lifeof about 30 days. After removal of the aluminum foil layer, the preciseshelf life of the container which includes the clear high-barrierlaminate film 64 depends necessarily on the moisture or oxygensensitivity of the drug contained in the intermediate compartment 23.Drugs with a relatively low moisture sensitivity are able to retainefficacy for periods substantially longer than 30 days by virtue ofbeing protected by the clear high-barrier laminate film 64. In addition,drugs with an extreme moisture sensitivity, i.e., those, that wouldnormally begin to lose effectiveness upon exposure to water vapor uponremoval of the aluminum foil layer, may be stored for periods up to twoweeks without loosing effectiveness because of the moisture barrierproperties of the clear high-barrier film overlying the intermediatecompartment 23.

Although the intermediate film 64 has been described in the exemplaryembodiment as being affixed to the outer surface of the medicamentcompartment, it will be apparent to one skilled in the art that theintermediate layer may be sized to cover both the intermediate and thefirst compartments if desired. The intermediate film 64 may also be usedto cover the entire front sheet 12. The manner of attachment of theintermediate layer 64 to the outer surface of the container may also bevaried without departing from the spirit or scope of the invention. Theintermediate layer 64 may be permanently secured to the outer surface ofthe container by a suitable adhesive, as well as by permanent heat orultrasonic sealing. Alternatively, the intermediate film 64 may beremovably provided on the surface of the container by adjusting thetemperature and pressure characteristics of a heat seal in order to makethe seal peelable. In this case, the film 64 could be peeled from thecontainer 10 as is the case with the opaque high-barrier laminate film55.

It should be noted that in the exemplary embodiment, the medicament isdescribed as being in the form of a liquid. The medicament may also bein the form of a colloid, crystalloid, liquid concentrate, emulsion, orthe like. In addition, the medicament may be provided as a dry powdersuch as antibiotic compositions or antiemetic compositions, withnon-limiting examples of such being; cefizolin, cefuroxime, cefotaxime,cefoxitin, ampicillin, nafcillin, erythromycin, ceftriaxone,metoclopramide and ticar/clav. The intermediate compartment 23 need notbe filled with a drug, per se. Other medical compositions such aslyophilized blood fractions, blood factor VIII, factor IX, prothrombincomplex, and the like, are particularly suitable for dispensing from acontainer in accordance with the invention. While the container of thepresent invention has been described with multiple compartments andparticularly, with a single medicament and diluent compartment, singlecompartment containers may be provided in accordance with the presentinvention as will be described in further detail below. In addition,containers which have multiple compartments filled with differentdiluents and/or different medicaments, may also be provided inaccordance with the present invention.

While preferred materials for the clear, high-barrier intermediate film64 would include both an oxygen barrier layer and a moisture barrierlayer, alternate materials may be used to provide a medicamentcompartment cover which is adaptable for various particular uses. Forexample, one of the high-barrier layers may be omitted giving ahigh-barrier intermediate film which includes only a moisture barrierlayer or only an oxygen barrier layer. Moreover, the high-barrierintermediate film 64 may include a moisture barrier layer, as describedabove, in combination with a heat sealed release layer which isconstructed from a high melting temperature material which also exhibitssome oxygen barrier properties.

Preferably, the flexible container 10 may be manufactured to aparticular overall size or to a few sizes. This limits the need forduplicate machines or alternatively multiple machine set-ups and runs.As previously discussed, a single overall container size, such as therectangular dimensions about the common peripheral edge 16, facilitatesthe handling of the container as well as the administering of thecontained medical solutions. In particular, this allows fabrication,handling, sterilizing and marking of the containers 10 to be carrier outwith similar or identical machines and procedures and eliminates theneed for multiple tooling and machine runs. However, restricting theoverall size of the container 10 limits the volume of medical solutioneach compartment can hold.

In order to increase the capacity of the container 10, and in accordancewith the principles of the present invention, at least one of the frontsheet 12 and the rear sheet 14 is elongated or otherwise permanentlystretched. Enlarging the volume capacity of the container 10 allows thefabrication of a single container design for storing and administering amuch wider variety and combination of medical solutions and medicines.Since the enlarged containers are unchanged from the conventionallysized containers, there is no need to tool up to manufacture thesespecially sized bags. This is especially advantageous where smallerquantities of containers may be needed which may otherwise not bemanufactured due to costs.

Referring now to FIG. 5, a conventional or standard sized container 10is shown with each of the front sheet 12 and the rear sheet 14permanently stretched to increase the capacity of the first compartment22. More particularly, the front sheet 12 and the rear sheet 14, eachinclude a respective surface area 70. These respective surface areas 70oppose each other across a common plane 71 which is generally definedalong the common peripheral edge 16. The front sheet 12 and the rearsheet 14 have been enlarged through a permanent stretching of therespective surface areas 70.

In the embodiment illustrated, only the first compartment 22 has beenenlarged. This configuration may be particularly useful when a greaterthan standard quantity of diluent is desired for use with a standardquantity of medicament. The front sheet 12 is stretched more or furtherelongated relative to the rear sheet 14. This is particularly true wherethe rear sheet 14 includes an aluminum or otherwise less expandablelayer.

Manufacture and Assembly of the Container

Referring now to FIG. 6, a method of manufacture and assembly of theflexible container 10 will be described in accordance with practice ofprinciples of the invention. The front sheet 12 and the rear sheet 14sheet are disposed opposing one another. The inward facing layer of thefront sheet 12 comprises an 80:20 film, which is placed in contact withthe inward facing 80:20 film layer of the rear sheet 14. Otherinterfacing films may be used and are within the scope and contemplationof the present invention.

The composition of the front and rear sheets 12 and 14 of the container10, allow for the creation of the seal along the common peripheral edge16 and the peelable seals 25 and 26 using heat sealing techniques. Hotbars or dies are used at differing temperatures, pressures andapplication times to bring interfacing portions of the materials andlaminates employed to temperatures near or above their melting points toallow migration of material across the interface to thereby form a bondof the desired strength and characteristics.

For either a single layer film, or a multi-layer laminate film,comprising the front sheet 12 and the aluminum foil laminate comprisingthe rear sheet 14, a procedure for fabrication of the container 10 isdescribed. The procedure comprises cutting the front and rear sheets ofthe container to the desired vertical container dimensions, butoversized in the horizontal dimension.

If the container 10 is being constructed with a single layer front sheet12, the high-barrier aluminum foil-containing protective layer 55 (ofFIG. 3) and the transparent high-barrier intermediate layer (64 of FIG.4), comprising the high-barrier covers for the second compartment 23 arecut to size, positioned over the area which will become the intermediateor medicament compartment, and sequentially attached to the container'sfront sheet 12. In accordance with the invention, the transparenthigh-barrier intermediate layer 64 is first laminated over the surfaceof the front sheet 12 followed by the aluminum foil-containingprotective layer 55.

Specifically, the transparent high-barrier intermediate layer 64 ispositioned over the second compartment 23 and held in place by a pair ofrods or similar devices while it is being laminated onto the surface ofthe front sheet 12. The portion of the layer 64 in contact with the rodsis, thus, not accessible to, for example, the heat seal head, resultingin a small portion of the film not being sealed onto the surface of thefront sheet. The residue of the use of rods to secure the transparenthigh-barrier intermediate layer in position a non-sealed area having thecontact footprint of the rod. The rod contact surface is generallycircular and results in two circular non-sealed regions 41 which remainvisible because of the reverse imprinting caused by pressure appliedduring the sealing process. Following lamination of the intermediatelayer 64, the aluminum foil layer 55 is applied over the surfacethereof, using a patterned heat sealing die as described above.

After attachment of the aluminum foil layer 55 and the transparenthigh-barrier layer, the front and rear sheets 12 and 14 may be matedtogether and permanently sealed together along the common peripheraledge 16. The outlet port 30 may include a flange 34 which is inserted inits desired final position between the front and rear sheets 12 and 14and fluidly connected with the outlet compartment 24. The outlet port 30may be injection molded and may have a composition of 40% FINA Z9450polyethylene-polypropylene co-polymer and 60% Shell Kraton™ G1652styrene ethylene-butylene styrene thermoplastic elastomer. Followinginsertion of the outlet port 30 along the common peripheral edge 16, aheated die is employed to create a permanent seal between the outletport flanges 34 and the bottom side 20 of the front and rear sheets 12and 14 adjacent the flange 34.

The peelable seals 25 and 26, and any additional peelable seal, dividingthe compartments and the container 10 are then created using, forexample, double hot bars comprising a front bar in alignment with a rearbar constraining the front and rear sheets 12 and 14 therebetween toform the seals 25 and 26. For example, the front bar may contact thepreviously combined high-barrier protective film 55, intermediate films64, and front sheet 12. This front bar is maintained at a temperature inthe range of about 245° F. to about 265° F. The rear bar, which contactsthe rear sheet 14, is maintained at substantially the same temperatureas the front bar (in the range of about 245° F. to about 265° F.) andmay optionally include a thin rubber coating to assure uniformapplication of pressure. The double bars are pressed into contact withthe front and rear sheets with a pressure in the range of from about 230psi to about 340 psi and maintained at that temperature and pressure fora period of time between about 1.5 to about 2.5 seconds. The peelableseals 25 and 26 may also be made individually with a single double barset up, or simultaneously with a twin double bar set up. Any additionalpeelable seals may be easily accommodated by a triple double bar set up.

Following the formation of the peelable seals 25 and 26, the front andrear sheets 12 and 14 are mated together and sealed by a peripheralpermanent heat seal which extends along the common peripheral edge 16.This permanent seal is spaced-away from the oversized edge of the firstside 27 of the container and provides openings between the front andrear sheets 12 and 14. In other words, the permanent seal is continuousalong the vertical upper side 18, the second side 28 and the verticalbottom side 20 and broken along the first side 27 to allow access to thefirst and second compartments 22 and 23. The permanent seal does notaffect the fluid connection of the outlet port 30 with the outletcompartment 24.

A first sacrificial port 72 may be inserted between the front and rearsheets 12 and 14 and fluidly connected with the first compartment 22. Ina similar configuration, a second sacrificial port 74 may be insertedbetween the front and rear sheets 12 and 14 and fluidly connected withthe second compartment 22. Preferably, each of the sacrificial ports 72are positioned and supported along the common peripheral edge 16 of thefirst side 27 within the gaps in the permanent heat seal. Thesacrificial ports may be supported by the common peripheral edge 16 in asimilar configuration to the outlet port 30. Thus, each of thesacrificial port 72 and 74 includes tapered mounting flanges 76 whichare interposed and sealed between the front and rear sheets 12 and 14along the common peripheral edge 16 of the first side 27. Thesacrificial ports 72 and 74 may be injection molded. Preferably, thesacrificial ports 72 and 74 are constructed from an inexpensivethermoplastic material, since they will be removed and disposed of at alater stage in the process. In a particular, the sacrificial ports 72and 74 may be constructed of 80:20 film “regrind” material, simplepolypropylene, or any other similar material.

The sacrificial ports 72 and 74 are an important feature of the presentinvention and provide a means for aseptically filling a singlecompartment container with a medical solution or a multiple compartmentcontainer with a liquid diluents in the first compartment 22 and amedicament or similar in the second compartment 23. In addition, thesacrificial ports 72 and 74 are provided with structure to allow theports and, thereby, the flexible medical container 10 to be supportedand manipulated by automated robotic machinery.

As depicted, each sacrificial port 72 and 74 includes a lower flange 78and a spaced apart upper flange 80. Each of the flanges 78 and 80 may begenerally rectangular or otherwise shaped to facilitate handling.Particularly, each of the flanges 78 and 80 may be particularlyconfigured for operation with support and handling equipment. An innerbore through each of the sacrificial ports 72 and 74 providescommunication with each of the respective compartments 22 and 23.

A generally cylindrical cap or plug 82 is provided for each of thesacrificial ports 72 and 74. The caps 82 may be constructed having anouter diameter which is slightly larger than the inner bore of each thesacrificial ports 72 and 74, such that when the cap 82 is inserted, theinterface between the cap outer diameter and the port inner diameterprovides a hermetic seal. This frictional seal is required to preventparticulates from entering the container 10 prior to filling and forpreventing powdered medicaments or liquid diluents from escaping afterthe container has been aseptically filled. Preferably, each of the caps82 may have a beveled bottom edge, so as to engage a similar chamfer oneach of the respective sacrificial ports 72 and 74.

In addition to the flanges 78 and 80 on the ports, a pair of verticallyspaced-apart flanges are also provided on the cap 82. In the exemplaryembodiment illustrated, a generally circumferential upper flange 84defines the top of the cap 82. The upper flange allows a “lifting”mechanism to engage the underside of the upper flange 110 and provide ameans to lift the cap vertically out of its respective port barrel 72and 74. A lower flange 86 may also be provided about the cap 82. Thelower flange 86 limits the penetration depth of the cap 82 duringinsertion into the port barrel 72 and 74 or when reseated after afilling operation. The lower flange 86 may be fully circumferential or,alternatively may be implemented as a partial flange defining a simplelateral extension from the body of the cap 82. The upper and lowerflanges 84 and 86 are spaced-apart from one another, along the body ofthe cap 82.

These manufacturing steps form the described flexible container 10having a conventional configuration with non enlarged compartments 22and 23. As previously discussed, the first compartment 22 may beenlarged to increase the available storage volume for diluent. In asimilar fashion, the second and the outlet compartments 23 and 24 mayalso be enlarged. This may include permanently stretching at least oneof the front sheet 12 or the rear sheet 14 by inflating the respectivecompartment 22, 23 and 24 with a pressurized gas as will be described ingreater detail below.

Container Fabrication Apparatus

In accordance with practice of principles of the present invention, aprocedure and apparatus for fabricating the container 10 of FIG. 6, willnow be described in connection with FIG. 7. As will be evident from thefollowing description of a container fabrication apparatus, both theapparatus and procedure are adapted to be suitable for manufacturingmedical containers with front and rear sheets comprising either singlelayer or multi-layer laminate films. In addition, it will be evidentfrom the following description that the number, shape, configuration andlocation of the various seals of the container 10 of FIG. 6, can beeasily changed, or indeed even omitted, due to the modular arrangementof components of the apparatus.

FIG. 7 is a semi-schematic plan view of an exemplary embodiment of acontainer fabrication machine 88 provided in accordance with the presentinvention, showing the arrangement and positioning of various sealforming stations and the arrangement and configuration of the containerprimarily film web supply rolls.

Bulk material for the container front and rear sheets (12 and 14 of FIG.2, for example) is provided to the container fabrication machine 88 inthe form of respective bulk film web supply rolls 90 and 92, which aremounted at web supply roll stations at the intake end of the containerfabrication machine 88. Web material from the, for example, front sheetsupply roll 90 is threaded through a dancer station 94 which functionsto maintain the web material at a proper tension as the web is drawnthrough the remaining stations of the fabrication machine 88.

Following dancer station 94, the web material is transported by vacuumfeed wheels past a first web cleaning station 96 and next through aseries of optional barrier film application stations 98 and 100,disposed serially along the web path. If the container 10 is beingconstructed in the manner described previously, i.e., to include asingle layer front sheet 12, a transparent high-barrier intermediatefilm (64 of FIG. 4) and a high-barrier aluminum foil-containingprotective layer 55, the high-barrier covers for the second compartment23 are first cut to size, next positioned over the portion of thesurface area 70 which will become the second compartment, and thensequentially attached to the front sheet 12 of the container 10 in thebarrier film application stations 98 and 100 respectively. In accordancewith the invention, the transparent high-barrier intermediate layer isfirst laminated over the surface 70 of the front sheet 12 in applicationstation 98 and the aluminum foil-containing protective layer 55 isoverlaid thereto in application station 100.

In a similar manner, web material which will form the container rearsheet is threaded from its respective bulk web supply roll 92 through acorresponding dancer station 102, and is transported by vacuum feedwheels through a corresponding web cleaning station 104.

When the continuous films of front and rear sheet web materials 90 and92 leave their respective preparation stages, they are fed intoregistration with one another and are oriented such that the 80:20surfaces of each continuous planar film faces the 80:20 planar surfaceof the other film. Once the continuous film webs 90 and 92 have been putinto registration, the web material is continuously indexed andlongitudinally moved through the seal core 106 of the fabricationapparatus 88. Sacrificial first (diluent) and second (medicament) ports72 and 74 are located along the web sandwich and positioned between thefront and rear sheet film webs, and various seals are sequentiallyformed on the web sandwich material so as to join the webs together andsubstantially fabricate the container 10 into an intermediate stagesuitable for expanding and aseptic filling, as best illustrated in FIG.6.

In accordance with practice of principles of the invention, thefabrication machine seal core 106 comprises a multiplicity of sealpresses and port insertion stations, arranged in series fashion alongthe travel path of the container film web sandwich. The first suchstation is a set port loading station 108, in which a set port, oroutlet port 30 is inserted in its proper position between the front andrear sheets 12 and 14. A heated press, including a shaped die, iscompressed over the web material to create a seal between the outletport flange 34 and the eventual lower edge of the front and rear sheetsadjacent the flange, at set port seal station 110.

The set, or outlet, port 30 is comprised of a plastic material and isinjection molded from a composition of 40% FINA Z9450 polypropyleneco-polymer and 60% Shell Kraton G1652 styrene ethylene-butylene styrenethermoplastic elastomer. Because of the similarities between thematerial composition of the set port 30 and the material of the inner,seal-forming surfaces of the front and rear sheet, it can be seen thatthe front and rear sheets may be sealed to the set port flange 34 usinga substantially similar heat seal regime, as that used for the formationof the permanent, peripheral seals, to be described in greater detailbelow.

Following insertion and sealing of the set port 30 to the containermaterial, the film web sandwich is next indexed to a sacrificial portinsertion station 112, at which sacrificial ports (72 and 74 in FIG. 6)are inserted between the front and rear sheets, in positions along thefirst side of the container and connected with locations which willbecome the first and second compartments 22 and 23. The sacrificialports 72 and 74 are preferably injection molded from a 100%polypropylene material but may also be fabricated of a material having acomposition similar to the composition of the outlet port 30. In amanner likewise similar to the outlet port 30, the front and rear sheetsare sealed to the sacrificial ports 72 and 74 along tapered flanges 76,which are provided for such purpose.

Following insertion of the sacrificial ports 72 and 74, the front andrear sheet film material is mated together by a permanent heat sealalong a portion of the common peripheral edge 16 which extends acrosswhat will become the top 18, bottom 20, and one continuous side 28 ofthe finished container. Along the opposite side 27 of the container 10,the permanent heat seal is provided parallel to, but spaced-away from,the peripheral edge 16 of the film web sandwich strip, and is formed inbroken-fashion along the desired edge of the finished container justinwardly from the common peripheral edge 16.

Following formation of the perimeter seal at the perimeter seal station114, the container material is indexed to a first, optional, medicamentsacrificial port seal station 116. The front and rear sheet material issealed to the tapered flange 76 of the second sacrificial port 74 bycompressing the front and rear sheet material to the tapered flange ofthe port by a pair of concave conformal heated sealing dies. As was thecase with the set port die, the heated sealing die of the second ormedicament seal station 116 is conformally shaped such that when the twohalves of the sealing die are compressed together, they form a generallyelliptical pocket having a shape which is the mirror image of the convextapered sealing surface of the second sacrificial port.

Next, the web material is indexed to a second, optional, firstcompartment sacrificial port seal station 118, where the front and rearsheet material of the container is compressed and heat sealed to thetapered flange 76 of the first compartment sacrificial port 72.

It will be appreciated that the order of sealing the sacrificial portsto the container is purely arbitrary and that the second sacrificialport seal station 116 may just as easily follow the first sacrificialport seal station 118 as vis versa. In addition, the seal stations forsealing the sacrificial ports 72 and 74 to the container 10 may precedeperimeter seal station 114. In addition, a further optional sealstation, peelable seal formation station 120 which is depicted in FIG. 7as following the sacrificial port insertion station 110 and precedingthe perimeter seal station 114, is optionally provided to form peelableseals between the first side 27 and the opposing second side 28 of thecontainer 10. The peelable seals bisect and subdivide the container 10into a plurality of compartments. Alternatively, the optional peelableseal station 120 may be configured to proceed the sacrificial portinsertion station 112, by merely repositioning the peelable seal stationalong the film web path. It will be evident as well, that a multiplicityof peelable seal stations may be provided, if the container is to befabricated with multiple compartments.

It should be evident to one having skill in the art, that thesequential, but independent, plurality of seal stations may each beconfigured to operate automatically as the film web is indexed to theirrespective stations. Alternatively, the seal stations may be present inthe container fabrication machine, but rendered inactive, such thattheir particular seals are not formed on a specific production run. Inparticular, a container may be fabricated without any peelable seals aswill be described in greater detail below. Following application of thesacrificial port seals, the container web material is indexed to a trimzone sealing station 122, which applies a permanent heat seal to thecontainer material which contacts and overlaps some of the brokenportions of the permanent seal along the common peripheral edge andextends to the edge of the container film material.

Following the heat seal process steps, the container may be indexedthrough a hanger punch station 124 or the like, which forms a hangercutout of the top center of the container. Following stations 126 and128 separate the containers by cutting the material web at the bottomend 20 (126) and then a top trim station 128 cuts away the containermaterial at the top end 18, following which the container is unloadedfrom the fabrication machine 88 and container construction issubstantially complete.

It will be evident to one having skill in the art that the number andconfiguration of compartments comprising the container is determinedsolely by the number and location of the various heat seals used to formthe container. In addition, depending on the number of containerscontemplated for the final product, a suitable number of sacrificialports are provided and positioned along their respective material webedges. It will be understood that the modular manufacturing processaccording to the present invention is adaptable to manufacture medicalcontainers having a single primary compartment, or multiple compartmentcontainers having any number of compartments, by merely providingadditional peelable seals and additional sacrificial ports with which tofill the compartments. For each configuration of compartments andsacrificial ports, the trim zone seal press at trim zone seal station122 may be suitably reconfigured by removing one press face andsubstituting another, which is configured to provide one, three, four orthe like channels or openings so as to connect a plurality ofsacrificial ports to a plurality of compartments.

In similar fashion, it will be clear to one having skill in the art thatthe composition of the container front and rear sheets may be changed bysuitably replacing the front and rear sheet film supply web rolls withother suitable materials. In particular, both the front and rear sheetsupply rolls may be single layer 80:20 film such that the finishedcontainer is transparent on both sides. Because of the modular nature ofthe fabrication apparatus, the clear barrier application station and thefoil barrier application station may both be rendered inoperable, aswell as the peelable seal formation station, thus configuring thecontainer fabrication machine to provide a single-compartment containerwhich is completely transparent, and which may comprise a multiplicityof outlet ports, such as separate med ports and set ports.

Accordingly, the container fabrication machine in accordance with thepresent invention is seen as being suitable for manufacturing a widevariety of medical containers, having a wide variety of sizes, and avariety of seal configurations and port locations. All of the containersso manufactured will be seen to be suitable for expanding to enlargetheir capacity and then for aseptic filling in accordance with theprinciples of the present invention as well as suitable for use incombination with a terminal sterilization procedure, if such is desired.

Seal Formation

The peelable seals 25 and 26 formed during the manufacturing processdescribed above are straight-line seals which have a thin, rectangularshape. While they appear similar to conventional straight-line seals,the peelable seals of this embodiment are improved in that they exhibita more predictable rupture characteristic across production lots, i.e.,they exhibit a uniform resistance characteristic to manipulationpressure.

Without being bound by theory, it is thought that the peelability of theseals is attained by limiting the time, pressure and temperature to thatnecessary to fuse the interface between the inner layers of the frontand rear sheets which have a lower melting temperature than theintermediate and outer layers of the rear sheet. The depth of thestructural alteration in the inner layers in the fusion zone is limited,thereby imparting the peelable character to the seal while providingsufficient strength to prevent breakage in normal handling of thecontainer. Preferably, the activation force for the container 10 of thepresent invention is tightly controlled to provide container integrityunder extreme handling conditions, yet be easy to activate for allusers. This activation effort or force is characterized by a burstpressure which is preferably approximately 4±1 lbs. pounds per squareinch (psi). However, this pressure may be slightly increased toaccommodate the larger volumes associated with the enlarged containersdescribed herein.

In order to achieve such uniformity in the burst pressure of a generallyrectangular seal, it has been determined that the critical parameterwhich must be controlled is temperature. Uniform burst pressure responseis achievable by controlling the seal temperature to within ±2° F.Commercially available production heat seal apparatus are not able tocontrol the variability in heat seal temperature to this desired range.However, the heat seal time is able to be controlled very precisely.Accordingly, time is chosen as the control parameter and adjusted tocompensate for the variation in heat seal temperature. Time and pressureof the seal head are monitored to ensure that they are within acceptableranges as described above and the heat seal time is adjustedaccordingly. While the contact pressure is preferably in the range offrom about 230 psi to about 340 psi, it will be recognized by one havingskill in the art that the lower figure in the range (about 230 psi) isprovided for convenience in setting the parameters of a production heatseal machine. So long as the pressure exerted by the heat seal bars onthe container material is sufficient to force the material seal layersinto contact over the surface area of the desired seal, a peelable sealwill be formed given an appropriate temperature and time. Indeed, it hasbeen experimentally determined that variations in heat seal temperatureand time beyond those contemplated by the present invention result inseals that not only fail to exhibit the desired uniform resistancecharacteristic, but also fail to rupture completely along the length ofthe seal. Incomplete seal rupture often results in residual diluent, forexample, remaining trapped in 90° corners where the peelable sealscontact the permanent peripheral seals of the container. Accordingly,the diluent/medicament mixture ratio may not be as expected, and drugdelivery may be at a higher concentration than desired.

Examples of specific time, temperature and pressure settings which willform peelable seals, in the 80:20 film of the illustrated embodiments,having a burst pressure of about 4±1 psi include: pressure 235 psi,temperature=257° F., and time=1.9 seconds; and pressure=235 psi,temperature=263° F., time=1.75 seconds.

Higher temperatures and associated pressures and times are used toprovide the peripheral permanent heat seals and the outlet port seal,which produce structure altering affects in a greater proportion to, ordepth of, the sealing layers. Such seals may be formed by heat sealingat a temperature of 290° F. and a pressure of up to 200 psi for abouttwo seconds. Those skilled in the art will recognize that varioustechniques for forming both permanent and peelable seals may be used inthe construction of the container of the present invention. Inparticular, it will be evident that controlling seal temperature to agreater degree (to within about ±2° F.) will also allow formation ofpeelable seals having uniform burst pressure. In addition, time ischosen as the control parameter for seal formation because it is able tobe precisely controlled. Precision control of temperature, pressure, orboth would give the same result.

Enlarging the Compartments

After the container 10 is brought to the stage of fabricationexemplified in FIG. 6, its volumetric capacity may be enlarged accordingto the principles of the present invention. In particular, any of thecompartments 22, 23 and 24 may be expanded or otherwise enlarged toincrease their volume capacity. For example, the first compartment 22may be permanently expanded in order to increase the quantity of storeddiluent. This may be particularly advantageous where a lower dosage ofmedicine is desired or where a more concentrated medicament is used.

The first compartment 22 may be expanded by stretching either the frontsheet 12, the rear sheet 14, or both, outwardly from the common plane70. This stretching elongates the film layers which comprise therespective front or rear sheet 12 and 14 in both the longitudinal andtraverse directions. The compartments 22, 23 and 24 may be elongated orotherwise stretched in different amounts to accommodate varyingincreases in volumetric capacity.

For example, and as best illustrated in FIG. 5 in conjunction with FIG.6, the first compartment 22 may be expanded by temporarily applying asupply of a pressurized gas to the first sacrificial port 72. Thepressurized gas inflates the first compartment 22 and applies anexpansion force over the surface area of each of the front and rearsheets 12 and 14. This force permanently stretches the materials of thefront and rear sheets 12 and 14. Preferably, the first compartment 22 ispermanently stretched or elongated in both the machine and transversedirections by the pressurized gas to the desired volume capacity. Tofacilitate the proper stretching and shape formation of each of thefront and rear sheet 12 and 14, a tool or form having shaped cavitiesmay be utilized as will be described in greater detail below. Thepressurized gas may include compressed air. However other compressedgasses or even liquids may be used. Preferably the pressurization gas is0.2 micron filtered air or nitrogen.

Referring now to FIGS. 8-10, an alternative, single compartment,embodiment of a flexible medical container constructed in accordancewith the principles of the present invention is shown. In thisembodiment, like features to those of the previous embodiment aredesignated by like reference numerals followed by the letter “a”. Asillustrated, a flexible container 10 a may be provided for combinedstorage and administration of a medical solution.

In this embodiment, the front sheet 12 a and the generally opposing rearsheet 14 a are sealed together along a substantial portion of the commonperipheral edge 16 a to form a single volume enclosure 17 a. If desired,the volume enclosure 17 a may be divided into two or more separatecompartments using peelable seals which extend from a first side 27 a ofthe common peripheral edge 16 a to an opposing second side 28 a of thecommon peripheral edge 16 a and separately join the front and rearsheets 12 a and 14 a together as previously described.

A pair of spaced apart sacrificial ports 72 a and 74 a may be supportedalong the first side 27 a of the common peripheral edge 16 and an outletport 30 a may be supported along the bottom 20 a. The ports 72 a, 74 aand 30 a are positioned between the front and rear sheets 12 a and 14 aalong the breaks in the permanent seal and heat sealed in place aspreviously described. The ports 72 a, 74 a and 30 a are advantageouslyprovided as part of this single compartment container 10 a to facilitatethe enlarging of the volume enclosure 17 a as well as for use withcommon handling and fabrication equipment. Thus, the ports 72 a, 74 aand 30 a and their fabrication may be identical to the previouslydescribed multi-compartment container.

The container 10 a is fabricated to a standardized or non-expanded size.At this stage in the fabrication process, the container may be enlarged,or alternatively may retain its as-fabricated non-expanded volumeenclosure and proceed to an aseptic filling step. In the example of FIG.8, the container 10 a may be fabricated having a substantially planarfront sheet 12 a constructed from a single polymer layer as previouslydescribed and a similarly sized opposing planar rear sheet 14 aconstructed from a multi-layer laminate as also previously described.The previously described transparent and opaque barrier layers have beenomitted. Without a compartment for a medicament, these barriers aregenerally unnecessary. However, these barrier layers may be added orotherwise provided if, as will be described below, amultiple-compartment embodiment with an enlarged compartment orcompartments, is desired.

The container 10 a of FIG. 8 suitably comprises a length or verticalheight along the first and second sides 27 a and 28 a of approximately8.25 inches and a width across the top and bottom 18 a and 20 a ofapproximately 5.25 inches. In this embodiment, the permanent seal alongthe common peripheral edge 16 a may define a volume enclosure 17 a withmaximum planar dimensions of approximately 7.0 inches by approximately3.5 inches. These dimensions are approximate and do not account for openspaces between the sacrificial ports 72 a and 74 a and the volumeenclosure 17 a. The described container 10 a thus, provides a surfacearea 70 a of approximately 24.5 square inches for each of the front andrear sheets 12 a and 14 a.

As fabricated, the single compartment container 10 a has a particularvolume capacity of approximately 130 to 150 ml [milliliters]. Forpurposes of example only, this capacity is defined by simply filling thevolume enclosure 17 a with a fluid and then measuring that quantity in agraduated cylinder. However, a larger volume capacity may be desiredwithin the general rectangular bounds of the described container. Asdiscussed, the overall capacity of the container 10 a may be greatlyincreased by stretching at least one of the front and rear sheets of thevolume enclosure 17 a. This may include stretching each of the sheets 12a and 14 a a different amount. Preferably, the expanded front and rearsheets 12 a and 14 a, are each stretched outwardly or away from a commonplane 71 a, as best illustrated in FIG. 9, to each form a curved surfaceas best illustrated in FIG. 10. As used herein, the term planar, inrelation to the front and rear sheets 12 a and 14 a refers to therespective sheets prior to being enlarged.

In some applications it might be desirable to stretch only one of thefront and rear sheets 12 a or 14 a. In those cases the front sheet 12 ais the most likely candidate for expansion. This is generally becausethe rear sheet 14 a includes a layer of an aluminum foil or similarbarrier layer and necessarily has a lower modulus of elasticity andgenerally, less responsive tensile properties. Since the front sheet 12a is a generally homogeneous layer with more responsive tensileproperties, greater stretching is achieved when elongating the frontsheet 12 a over the rear sheet 14 a. In addition, the rear sheet 14 a isoften used for markings, including administration and mixinginstructions. Printing may be less effective on a stretched and curvedsheet. Reading the printed information on a permanently stretched curvedsheet may also prove difficult. However, in particular applications, therear sheet 14 a may also be solely stretched.

Pertinent to the elongation of either the front sheet or rear sheet 12 aor 14 a, the container fabricated in accordance with the presentinvention, is the recognition that the front and rear sheet's elongationcharacteristics depend on the particular materials from which they arefabricated. The physical tensile properties of the various single andmulti-layer laminate films used in constructing a medical containerrelatively easily determined by the methods set forth in the ASTMD-882-81 specification. Typical tensile properties of various componentsof the single and multi-layer films described above are available fromthe film manufacturer via the particular film's technical data sheets.For example, KRATON G1652 styrene ethylene-butylene styrene elastomerhas a typical tensile strength of about 4500 psi, exhibits anapproximately 500% elongation at break, and has a modulus of about 700psi at 300% extension. Similarly, Fina Z9450 copolymer has a typicaltensile strength of about 2500 psi, while the aluminum foil layer (ALCAN1145) has a typical tensile strength of approximately 9300 psi (0.001gauge) and a typical elongation characteristic (at 0.001 gauge) of about4.2%. It will be well understood by one having skill in the art thatother films having different tensile strengths and different elongationcharacteristics will necessarily be expandable to a correspondinglygreater or lesser degree than the films referred to above. Suchdiffering elongation characteristics are easily calculable with recourseto ordinary test data taken at uniform jaw separation rates, uniformtemperatures and uniform specimen shapes such as a dumbbell specimen cutwith an ASTM die C.

Referring now to FIGS. 11-12, an embodiment of a tool or form 130 inaccordance with the present invention will be described for use withenlarging the container 10 a of the present invention. The tool 130 isconfigured for receiving at least a portion of the volume enclosure 17a. The tool 130 includes an upper tool portion 132 and an opposing lowertool portion 134. In the illustrated embodiment, the lower tool portion134 has an internal cavity 136 and the upper tool portion 132 has anopposing internal cavity 138. A planar outer surface 140 surrounds eachof the cavities with the exception for an opening 142 at one of theports 72 a, 74 a and 30 a. Other tool configurations may include a toolportion 132 or 134 which is not provided with a cavity, but has asubstantially planar surface. This configuration is advantageous whenonly expanding one of the front and rear sheets 12 a and 14 a. Otherconfigurations include altering the size and shape of each cavity 136and 138 to conform the shape of the elongated front and rear sheets 12 aand 14 a.

The tool 130 may also include coupling devices 144, such as dowels andcorresponding bores to ensure the upper and lower tool portions 132 and134 remain stationary and interlocked during use. However, any otherdevices or methods may be used to retain the top portions 132 and 134aligned and together. A sealing lip 146 may circumferentially surroundat least one of the cavities 136 and 138 and follows the seal footprintof the compartment being expanded. The sealing lip 146 maintains thefront sheet 12 a and the rear sheet 14 a together during the expansionprocess and retains the pressurized gas within its boundary. Thisprevents the inflation forces from being substantially transferred intothe permanent seal along the common peripheral edge 16 a. The sealinglip 146 may incorporate an o-ring or similar device and may be providedon each tool portion 132 and 134 or alternatively, on only one of thetool portions. The sealing lip 146 is preferably broken or otherwiseinterrupted around the opening 142. This allows the pressurized gas intoand out of the volume enclosure 17 a. Preferably, the opening 142 islocated adjacent one of the ports 30 a, 72 a or 74 a to allow inflationand deflation through that port.

In the embodiment illustrated in FIG. 11, the tool 130 is configured toreceive the entire volume enclosure 17 a of the single compartmentcontainer 10 a. The container 10 a is placed on the lower tool portion134 with the outer surface of the front sheet 12 a facing into the lowercavity 136 and the common peripheral edge 16 a supported by the planarsurface 140. The sealing boundary 146 is aligned just inside of thepermanent seal along the common peripheral edge 16 a. A pair of spacedapart sacrificial port slots 148 are disposed along a common side ofeach of the tool portions 132 and 134 and are each configured to receiveone of the sacrificial ports 72 a and 74 a. An outlet port slot 150 isdisposed along a second common side of the tool portions 132 and 134 andis configured to receive the outlet port 30 a.

Once the container 10 a is aligned within one of the tool portions 132and 134, and preferably, the lower tool portion as described above, theopposing tool portions may be brought together. The upper tool portion132 may be placed against the lower tool portion 134 and aligned suchthat the outer surface of the rear sheet 14 a is facing the upper cavity138 and the ports 30, 72 a and 74 a are received within the port slots148 and 150. The planar surface 140 of the upper tool portion 132 isseated against the planar surface 140 of the lower tool portion 134 andrestrainably sandwiches the entire common peripheral edge 16 a with theexception of the opening 142. The opening 142 allows passage of thepressurized gas into and out of the first sacrificial port 72 a. Thesandwiched container 10 a, may now be inflated with the pressurized gasto inflate the volume enclosure 17 a and forcibly expand the front andrear sheets 12 a and 14 a against the cavities 136 and 138.

The tool 130 may also be provided in any other number of configurationsas may be determined by those of skill in the art and thus, theexemplary embodiment is not meant to be limiting. Additional exemplaryembodiments may include a tool having different sized upper and lowercavities or a tool with one tool portion having a cavity and theopposing tool surface being planar. This embodiment may be particularlyuseful where only one of the front and rear sheets 12 a and 14 a are tobe stretched. Alternatively, the tool may have a number of differingcavities within each tool portion for use with multi-compartmentcontainers. This embodiment may require an opening into each of thediffering cavities for inflating the different compartments and planarsurface sections on each of the tool portions for supporting thepeelable seals defining each of the compartments. When enlarging only asingle compartment of a multi-compartment container, each portion of thetool may include only a single cavity, but of a size just less than thecompartments outer diameter, for example.

The sacrificial port slots 148 and the outlet port slot 150 may beconfigured to align the container 10 a within the tool 130. Thus, theymay include grooves for receiving the flanges 78 a and 80 a on thesacrificial ports 72 a and 74 a or have other configurations for fixablylocating each of the ports. Alternatively, only one or two of the portslots 148 and 150 may be so configured. However, other devices andmethods may also be used for aligning the container 10 a within the tool130 as is known to those of skill in the art. For example, alignmentgrooves may be provided along the planar surface 140 for receiving theat least a portion of the top, bottom or sides 18 a, 20 a, 27 a, and 28a of the container 10 a. Alternatively, a slot, notch or other alignmentdevice (not shown) may be provided on the container 10 a and acomplimentary alignment post or the like may be provided on the tool130.

In a preferred embodiment, the tool 130, with the captured container 10a, is actuated on by an expansion machine 152 for inflation andenlargement, as best illustrated in FIG. 13. Preferably, the expansionmachine 152 includes a table or operating base 154 for receiving andhandling the tool 130. The tool 130 is then placed into a mouth 156 ofthe machine 152. Once inside the machine 152, cylinders 157 are used toclamp or otherwise maintain the opposing tool portions 132 and 134together. The cylinders 157 can be hydraulic, electric motor driven, andthe like, but are preferably pneumatic. Other devices and methods, suchas pressure clips, may also be used to maintain the tool halves togetherduring the expansion process.

A supply of a pressurized gas 158 is coupled to the opening 142 withinthe tool 130 and the container 10 a is inflated with the pressurized gas158 to fully expand the front sheet 12 a into the lower cavity 136 andthe rear sheet 14 a into the upper cavity 138. This expansionpermanently stretches and permanently elongates both the front sheet andthe rear sheet 12 a and 14 a outwardly from the common plane as definedby the common peripheral edge 16 a within the tool 130. The pressurizedgas 158 may be maintained within the tool 130 for a brief period of timeto maintain the front and rear sheets 12 a and 14 a against therespective cavities 136 and 138. Maintaining the volume enclosure 17 ainflated reduces the amount of shrinkage or elastic rebounding.Typically, for the previously described film construction materials,this period is less than a minute. The pressurized gas 158 may then berelieved, the tool 130 removed from the expansion machine 152 and theenlarged container 10 a removed from the tool 130. Preferably, thisexpansion operation is automated.

In the illustrated embodiment, the container 10 a is expanded from aninitial volume capacity or non-enlarged capacity of approximately 130 to150 ml, to an enlarged volume capacity of approximately 250 to 300 ml asvolume capacity is defined herein. Preferably, the container 10 a isenlarged to a volume capacity of approximately 260 to 280 ml and morepreferably to approximately 280±5 ml. To achieve these particular finaldimensions on a single compartment container exemplified in FIG. 8, theupper and lower tool cavities 136 and 138 are configured to have afootprint area corresponding to the compartmental area of the container,i.e., approximately 7 inches by approximately 3.5 inches, and are eachhollowed-out to a depth sufficient to define a volume of approximately300 ml for the lower tool cavity 136 and a volume of approximately 100ml for the upper tool cavity 138. Specifically, lower tool cavity 136 ishollowed-out to a depth of approximately 1.5 inches, while the uppertool cavity 138 is hollowed-out to a depth of approximately 0.6 inches.In addition, the sides of each of the cavities are blended into thecavity bottom with a continuous curvature so as to minimize any “hardcorners” into which the container material might be forced, therebydistending the material.

Thus, the opposing tool cavities 136 and 138, when combined together,have a total volume of approximately 400 ml and a longitudinalcross-sectional area of approximately 24.5 square inches. These volumesand areas are not strictly precise, because the regions within the portslots 148 and 150 have necessarily not been taken into account. Itshould also be noted that due to the greater depth of the lower toolcavity 136 (and its consequent increased volume), the front sheet 12 awill be allowed to stretch to a considerably greater degree than therear sheet 14 a. The reason for the difference in volume capacitybetween the upper and lower tool cavities is because the front and rearsheet materials are expanded until they contact the inner surfaces ofthe cavities. The depth of each cavity and its corresponding volume areconfigured to correspond to the typical tensile properties of the filmwhich will be expanded into that cavity.

The volume enclosure 17 a is preferably inflated with compressed air,having a pressure of between approximately 10 and 30 psi. for a periodof approximately 1 to 30 seconds. Pressures of less than 10 psi may beused, however, the force developed is generally not sufficient topermanently stretch the described front and rear sheets 12 a and 14 aagainst the cavity. Utilization of differing materials, such as acontainer having two homogenous layers similar to the described singlelayer front sheet 12 a, may allow effective stretching at 10 psi orlower. Pressures of approximately 30 psi and above tend to rapidlyexpand the front and rear sheets 12 a and 14 a against the cavities 136and 138. This rapid expansion may stretch the material too fast whichcan lead to wrinkled material, delaminations within the laminate rearsheet 14 a and other undesirable effects. It may be possible to utilizehigher pressures by slowly or incrementally inflating the volumeenclosure 17 a in steps or alternatively, by heating the compressed gas.The sheet being expanded or the surfaces of the cavity may also beheated. These and other methods and devices may be used to modify thepreferred pressures and times necessary to achieve the desired enlargedcapacity for the container 10 a as is known to those of skill in theart.

In a preferred embodiment, the volume enclosure 17 a is inflated withinthe described tool 130 using compressed air regulated at a pressurebetween approximately 15 and 25 psi for between 15 and 25 seconds. Morepreferably, the pressure is regulated to approximately 20 psi andmaintained for approximately 15 seconds at ambient temperature.Increasing the pressure or time can additionally stretch each of thefilms if the volumetric capacity of the expansion tool werecorrespondingly increased. This increased expansion would, of course,provide an increased volume in an expanded container. Likewise,decreasing the pressure or time results in reduced expansion and smallervolume capacities. These preferred parameters expand the front sheet 12a fully against the 300 ml lower cavity 136 and the rear sheet 14 afully against the 100 ml upper cavity 138 and result in an overallenlarged capacity of approximately 280 ml plus/minus 5 ml. Shrinkage dueto the relaxation modulus in the materials results in the enlargedcapacity of the container 10 a being less than the combined volume ofthe cavities 136 and 138. In order to minimize further shrinkage, adeblocking process may be utilized as will be described in greaterdetail below.

The exemplary enlarging process described results in the surface area ofthe front sheet 12 a being enlarged approximately 10% and the rear sheet14 a being enlarged approximately 6%. However, the preferred materialsmay be capable of being permanently deformed to much greater amounts,allowing for fabrication of containers having even greater volumecapacities. For example, the surface area of the front sheet 12 a,comprising the preferred 80:20 material, may be enlarged up to at leastapproximately 16% while the surface area of the rear sheet 14 a, madefrom the preferred laminate material, may be enlarged up toapproximately 10%. The surface area of the front sheet 12 a, comprisingthe preferred 80:20 material, can be enlarged more than the surface areaof the preferred rear sheet 14 a due, in part, to the low elasticity ofthe aluminum layer in the laminate structure of the rear sheet.

Once the container 10 a has been enlarged, it is de-blocked. Thisprocess maintains a volume of a gas within the enlarged volume enclosure17 a sufficiently to maintain the enclosure in an expanded condition.Deblocking prevents the enlarged volume enclosure 17 a from furthershrinkage due to the inherent elasticity in the materials as defined bytheir relaxation modulus. This may be particularly advantageous for thefront sheet 12 a which is typically expanded to a greater elongation andis not supported by an adhered aluminum layer.

Deblocking includes inflating the container 10 a with a low pressure gasto ensure the volume enclosure 17 a is fully expanded to the enlargedconfiguration. The low pressure gas may comprise compressed airregulated to a few psi. However, other gases such as dry nitrogen mayalso be used. Preferably, the deblocking pressure is regulated to belowapproximately 10 psi, and more preferably to between about 1 to 5 psi.This prevents continued shrinkage, stress on the seals and the like.Once the volume enclosure 17 a is fully expanded, the sacrificial ports72 a and the outlet port 30 a are capped. Further shrinkage of thevolume enclosure 17 a will now meet resistance in the form of gaspressure within the sealed volume enclosure 17 a. Deblocking may takeplace within the expansion machine 52. However, a deblocking station maypreferably be provided.

An additional embodiment of a medical container fabricated with anexpanded compartmental volume will now be described with reference toFIGS. 6, 11 and 12. FIG. 6 is a semi-schematic front view of aparticular embodiment of a multiple-compartment container at the samestage in its fabrication process as the single compartment containerillustrated in FIG. 8. The multiple-compartment container of FIG. 6differs from the single compartment embodiment in that peelable seals 25and 26 span the container and extend between the permanent peripheralseals 16 on either side of the container, to define an intermediatecompartment 23 for containing a, for example, medicament. The peelableseals 25 and 26 also function to delineate a separate compartment 22 forcontaining a liquid diluent and an outlet compartment 24 which isinitially empty. A multiple compartment container according to theembodiment of FIG. 6 and fabricated with the films and techniquesdescribed above, is capable of holding a relatively limited volume ofdiluent liquid in the diluent compartment 22. The multi-layer laminaterear sheet is a relatively stiff barrier material, as mentioned above,the stiffness of which limits the volume of diluent that can beintroduced into the diluent compartment 22 to approximately 60 ml.Indeed, containers of the type illustrated in FIGS. 1 and 6 are commonlymarketed as 50 ml containers, i.e., containing 50 ml of liquid diluentfor mixing with a medicament prior to dispensation. The efficiency ofvarious infusion therapies commonly require IV containers to be able tohold a substantially greater volume than the approximately 60 ml volumeof the diluent compartment 22 of the container of FIGS. 1 and 6.Specifically, a PAB container manufactured and sold by McGaw, Inc. ofIrvine, Calif. is commonly used to hold 100 ml of a 0.9% sodium chloridesolution, in a condition termed partial fill. Thus, it can be seen thatexpanding the diluent compartment 22 of a multiple compartment containeras illustrated in FIGS. 1 and 6 is particularly desirable.

As has been described above, in connection with the embodiment of FIG.8, the container is confined within a tool having a hollow interiorcavity, or cavities, and inflated with a pressurized gas to therebystretch the material of the container's front and rear sheets(alternatively, the front sheet only) to permanently expand a particularcompartment's volumetric capacity. The process and apparatus describedin connection with FIGS. 9-13 are equally suitable for use in connectionwith the multiple compartment container of FIG. 6. All that is requiredis that the areal footprint of the top and bottom cavities 136 and 138be reduced, or modified, to conform to the footprint of the diluentcompartment 22 of the multiple compartment container 10 of FIG. 6.

The diluent compartment footprint, as that term is used herein, isgenerally rectangular in shape and is defined, on three sides, by thepermanent peripheral seal 16 and, on the fourth side, by the peelableseal 25 which separates the diluent compartment 22 from the medicamentcompartment 23. Neglecting the channel 41 formed between the diluentcompartment 22 and its corresponding sacrificial port 72, thecompartment footprint would describe a rectangle which is approximately3.5 inches wide and approximately 5.0 inches long. Accordingly, thesealing boundary (146 of FIG. 11) is configured and dimensioned toconform to the seal footprint of the diluent compartment 22 of themultiple compartment container of FIGS. 1 and 6.

Because the seal 25 separating the diluent compartment from themedicament compartment is a peelable seal, particular care should betaken to ensure that the sealing boundary (146 of FIG. 11) is configuredto lie slightly inside the seals, particularly the peelable seal 55.Recalling that the peelable seal is designed to burst under pressure, itwill be recognized that providing the sealing boundary 146 inside theseal footprint and particularly inside the footprint of the peelableseal 55, forms a pressure stop against application of a burst pressureto the peelable seal.

In a manner similar to that described in connection with the embodimentof FIG. 8, the diluent compartment 22 of the multiple compartmentcontainer of FIGS. 1 and 6 may be expanded by stretching either thefront sheet 12 the rear sheet 14, or both. Because of thecharacteristics of the films used to form the front and rear sheets, 12and 14, it will be understood that the front sheet 12 is expandable to agreater degree than the rear sheet 14 under the same time and pressureregime as that described in connection with FIG. 8.

The tool embodiment for use in expanding the diluent compartment of amultiple compartment medical container is generally quite similar to thetool embodiment described in connection with FIGS. 11 and 12. However,because of the smaller areal footprint (3.5 inches×5 inches as opposedto 3.5 inches×7 inches) of the diluent compartment versus the entirecontainer, the depths of the top and bottom cavities 136 and 138 arecorrespondingly reduced, so as to not over-stretch the diluentcompartment film materials. As described above, the bottom cavity 136has a footprint of approximately 3.5 inches×5 inches and a cavity depthof from about 0.75 inches to about 1.0 inches to define the cavityvolume of from about 160 ml to about 175 ml. Preferably, only the frontsheet is stretched in the embodiment of FIG. 6, so the top tool portioncomprises a substantially flat surface which is not provided with thecavity. However, were a cavity to be provided, it would have a footprintof approximately 3.5 inches×5 inches and a cavity depth of from about0.25 inches to about 0.35 inches to define the cavity volume of fromabout 50 ml to about 60 ml. Providing the cavities in such manner,allows the diluent compartment 22 to be expanded from its nominal 50 mlstandard capacity to an approximately 100-150 ml volume capacity, asthat term has been defined previously.

Once the multiple compartment container of FIGS. 1 and 6 has beendisposed with an appropriate inflation tool, the diluent compartment isinflated through its corresponding sacrificial port (72 of FIG. 6) by0.2 micron filtered air or nitrogen at an inlet pressure ofapproximately 20 psi. The diluent compartment is maintained in aninflated condition for approximately 15 seconds to allow time for thefilm to stabilize in its stretched condition. Following volumetricexpansion, the multiple compartment container is now ready to besterilized, aseptically filled, trimmed to its final dimensions andshipped to the ultimate consumer.

Sterilization, Filling and Final Container Formation

After the container 10 a has been enlarged to the desired volumecapacity or capacities, it preferably has the configuration exemplifiedin FIG. 8. The container 10 a is now in a condition for sterilizationand aseptic filling with a medical solution. After sterilization andfilling, the sacrificial ports 72 a and 74 a may be removed, leaving afinished enlarged container as best illustrated in FIG. 17.

In an exemplary filling process, the particular embodiment of thecontainer to be filled, in accordance with the invention, is one whichincorporates a single layer front sheet film 12 a and a multi-layeraluminum foil laminate rear sheet film 14 a. The front and rear sheets12 a and 14 a have been formed to comprise a volume container 17 a whichhas portion of the common peripheral edge 16 a left unsealed for fillingthrough the respectively provided sacrificial ports 72 a and 74 a. Thisembodiment of the container 10 a at this stage of fabrication is bestdepicted in FIG. 8. Primary container fabrication, including theprovision of an outlet port 30 a and sacrificial ports 72 a and 74 a, isaccomplished by the method and apparatus previously described.

In order for an aseptic filling process to be acceptable for medicalpurposes, the unfilled container 10 a must be provided in a sterilecondition. Conventionally, container sterilization takes place in aseparate processing area or facility due to the rather extensive andcomplex equipment and processes required for sterilizing material. Aparticular undesirable feature of the sterilization procedure is thatthe container must be transported to the sterilization facility forprocessing, following which container sterility must be maintainedduring subsequent storage and transport to an aseptic filling facility.The container must be introduced into the aseptic filling zone by meansof a sterile transfer in order to prevent contamination of the asepticzone by the container. Once introduced into the aseptic zone, thecontainer may be filled aseptically, but must be further handled in asterile fashion.

In accordance with practice of principles of the invention, followingprimary container fabrication, a plurality of empty containers areloaded into a handling container which is then sealed to protect theflexible containers 10 a contained within from environmentalcontamination.

Turning now to FIG. 14, a transport or handling container, generallyindicated at 160 and termed “a carrier” herein, functions as atransportable sterile containment isolator for sterilizing, transportingand introducing into the aseptic zone, empty containers in a systematicmanner. The carrier 160 comprises three components; a generallyrectangular container tray 162, a sealable film lid 164, and a railcartridge 166 for supporting a multiplicity of containers 10 a withinthe tray and which will be described in greater detail below. Thedescribed carrier 160 is merely an exemplary embodiment and otherconfigurations may also be utilized as will be known to those of skillin the art.

The generally rectangular container tray 162 may be constructed of athermoformed polystyrene material or other material capable ofwithstanding several sterilization cycles without significantdegradation. The tray 162 may be shaped generally in the form of a basinwith its upper peripheral edge bent-over outwardly to form a flat,horizontally oriented peripheral lip or flange 168 which extends beyondthe sides of the tray 162 for a distance of between about ¼ inches toabout 1 inch. Preferably, the lip 168 extends about ¾ inches beyond thesides of the tray, but any extension which provides rigidity to the tray162 and a sufficient surface to support a seal is suitable. Two opposingpockets 170 and 172 are formed in about the centers of the two opposingshort sides of the tray and extend outward from the plane of the shortsides. The pockets 170 and 172 extend only partially downward along thesides of the tray and form, thereby, two opposing recesses into whichthe ends of the rail cartridge 162 may be inserted. The rail cartridge166 rests on the bottom surfaces of the pockets 170 and 172 and isthereby suspended above the bottom of the tray 162 at a heightsufficient to allow containers 10 a arranged on the rail cartridge tohang free within the interior volume of the tray. Accordingly, thepockets 170 and 172, in combination with the rail cartridge 166,functions to maintain a multiplicity of containers 10 a in a specificorientation during transport, storage and UV sterilization.

Once the rail cartridge 166 has been loaded with containers 10 a andinserted into the pockets 170 and 172, the tray 162 is environmentallysealed by heat sealing the plastic film lid 164 to the tray flange orlip 168 in a distinct orientation. For illustrative purposes in FIG. 14,the film lid 164 is depicted half way through the sealing process, witha portion of the lid lifted up to show the rail cartridge 166 nestedwithin the tray 162. The film lid 164 is positioned on the flange 168such that there is no “overhang” of the film lid material over the edgeof the tray flange around the perimeter of the tray. In an exemplaryembodiment, the plastic film lid 164 is constructed to have dimensionswhich allow the film lid to be positioned on the tray flange 168 suchthat the film lid edge is inset from the tray flange edge around theentire flange periphery. In addition, the film lid heat seal is appliedto extend beyond the edge of the film lid 164, to assure that no portionof the film lid edge left unsealed that would create a loose edge“flap”. Film lid orientation, placement and the avoidance of loose edgesis particularly important to the surface ultraviolet (UV)decontamination process performed on the carrier 160 when the carrier isintroduced to the aseptic zone. Crevices, caused by loose film lid edgesand/or flaps, may cause a local shadow, when exposed to UV radiation,which shadowing effect can defeat the UV decontamination process.

Once the film lid 164 has been heat sealed to the tray flange 168, thecarrier 160 defines a hermetically sealed environment that functions toisolate its contents from external contamination. The carrier 160 maythen be placed into a polybag overwrap or similar covering (not shown),which acts a “dust cover”, and identified with an adhesive label whichis placed on the over wrap.

Referring now to FIGS. 15 and 16, a carrier rail cartridge 174 maycomprises a plurality of injection molded, polystyrene T-beams 176disposed at spaced-apart intervals so as to form longitudinally runningslots 178 therebetween. Fabricated containers 10 a may be loaded ontothe cartridge 174. The containers 10 a, such as those depicted in FIG.8, are loaded onto the carrier rail cartridge 166 by inserting theirsacrificial ports 72 a and 74 a into the slots 178 formed between thecartridge's T-rails 176. The T-rails 176 may have edges which arespaced-apart a sufficient distance (about 13.0 mm) such that the centralfilling barrel of each sacrificial port 72 a and 74 a is able to beaccommodated therebetween, and are adapted to engage the sacrificialports between the port's circumferential flanges (78 a and 80 a) suchthat each container 10 a is grasped by the T-rail flanges 176 beneathits uppermost circumferential sacrificial port flange 80 a.

In the exemplary embodiment of the carrier rail cartridge depicted inFIGS. 15 and 16, four slots 1178 are provided for receiving containers10 a, with the containers loaded onto the rail cartridge 166 inalternating left and right orientations. The sacrificial ports 72 a and74 a of each container 10 a are inserted into two of the slots 178. Afirst container may be loaded into a second and fourth slots andoriented in a first horizontal direction. A second container may then beloaded onto the rail cartridge 166 with its sacrificial ports 72 a and74 a inserted into a first and third cartridge slots 178. The secondcontainer 10 is loaded in a second horizontal direction oriented 180°with respect to the first container. Further containers 10 a are loadedonto the carrier rail cartridge 166 in like fashion, with thecontainer's horizontal orientation alternating left and right; thesacrificial ports of the left oriented containers inserted into thesecond and fourth slots, the set ports of the right oriented containersloaded into the first and third slots, as described above, until thecarrier rail cartridge 166 is completely filled. Obviously, each carrierwill support a larger number of pre-enlarged containers than enlargedcontainers.

Following loading, the carrier rail cartridge 174 is placed within thetray 162 with the ends of the T-rails 176 nested in the pockets 170 and172 formed in the ends of the tray. Pockets 170 and 172 support thecarrier rail cartridge 166 within the interior volume of the tray andprovide additional lateral support which prevents the cartridge fromshifting during shipping, sterilization and storage.

The sealed carrier, including the empty containers within, is wrapped ina poly bag or similar container for radiation sterilization where thecarrier 160 and the retained containers 10 a are rendered sterile by anE-beam sterilization procedure or the like. After the foregoing carrierloading and E-beam sterilization procedure is completed, the sterilizedmedical containers 10 may be aseptically filled with a medical solution.This may include transporting the carrier 160 and the retainedcontainers 10 a to an aseptic filling station. Filling of the volumeenclosure 17 a may be accomplished using the technique of relatedco-pending application Ser. No. 08/837,927 filed Apr. 11, 1997, whichdisclosure is herein fully incorporated by reference. These techniquesmay be applied to a single medical solution or alternatively to fillingmultiple compartments.

After sterilization and filling, the fabrication of the enlargedcontainer of FIG. 8 may be completed by removing the sacrificial ports72 a and 74 a and completing the permanent seal around the first side 27a of the common peripheral edge 16 a. The finished container 180includes an increased capacity for storing a medical solution relativeto a standard or non-enlarged container.

The final fabrication process includes removing a portion of the firstside 27 a of the container 10 a just inward from the sacrificial ports72 a and 74 a and including the sacrificial ports. Each of the fluidconnections or passageways between the sacrificial ports 72 a and 74 aand the volume enclosure 17 a is then sealed. This is accomplished byapplying a permanent seal, similar to that previously described, acrossthe first side 27 a just inwardly from the common peripheral edge 16.This permanent seal completes the volume enclosure 17 a. When using amultiple compartment container, the permanent seal may be applied acrosseach sacrificial port 72 a and 74 a after each respective filling. Aportion of the first side 27 a, including the sacrificial ports 72 a and74 a may then be removed. As can be seen relative to the differencesbetween FIG. 8 and FIG. 17, the removed portion includes the sacrificialports 72 a and 74 a and a narrow strip of the first side 27 a of thecontainer 10 a.

Those skilled in the art will recognize that the primary discussion ofembodiments comprising a liquid diluent and a single powdered medicamentas well as a single volume enclosure embodiment do not limit the scopeof the invention. Use of liquid medicaments in the intermediatecompartment or a plurality of compartments for powdered and liquidmedicaments, to be mixed with the diluent, may be employed using thepresent invention. Multiple sacrificial ports and communication channelsbetween the sacrificial ports and a respective compartment may easily beprovided in accordance with practice of principles of the invention.Moreover, depending on the susceptibility of any of the componentscomprising the contents of the multiple compartments to moisture or freeoxygen contamination, those compartments may be protected by additionalapplications of a clear, transparent SiO_(x) containing, high-barrierlaminate over the container front sheet in those compartment regions.Such high-barrier laminates may be provided with or without beingcombined with an aluminum foil containing high-barrier laminate peelablecovering.

The above descriptions of exemplary embodiments of flexible, sterilecontainers are for illustrative purposes. Because of variations whichwill be apparent to those skilled in the art, the present invention isnot intended to be limited to the particular embodiments describedabove. Such variations, and other modifications and alterations areincluded within the scope and intent of the invention as described inthe following claims.

What is claimed is:
 1. A method for increasing the capacity of aflexible container for storage and administration, the method comprisingthe steps of: providing a pair of flexible planar sheets; joining theflexible planar sheets together to thereby provide a flexible containerhaving a flexible planar front sheet opposing a flexible planar rearsheet along a common plane, the front sheet being sealably attached tothe flexible rear sheet along a common peripheral edge to form a volumeenclosure and having an outlet port formed along the common peripheraledge for emptying stored contents; and expanding the volume enclosure byintroducing a pressurized fluid through a sacrificial port and into thevolume enclosure to permanently stretch at least one of the front orrear sheets to thereby increase the capacity of the volume enclosure,the sacrificial port being separable from the flexible containersubsequent to the expanding step.
 2. The method as recited in claim 2wherein the pressurized fluid is a gas.
 3. The method as recited inclaim 2 wherein the step of expanding comprises the steps of:maintaining the rear sheet and the common peripheral edge substantiallyagainst the common plane; and inflating the volume enclosure with apressurized gas to permanently stretch a portion of the front sheetoutwardly from the common plane.
 4. The method as recited in claim 1wherein the step of expanding comprises inflating the volume enclosurewith a pressurized gas to permanently stretch both the front and therear sheets.
 5. The method as recited in claim 4 wherein the stretchedvolume enclosure supports a volume capacity of at least two times theprovided container.
 6. A method for constructing a flexible containerfor combined storage and administration, the method comprising the stepsof: a. providing a substantially transparent front sheet constructedfrom a planar layer comprising a polymer; b. providing a flexible rearsheet constructed from a vapor impermeable layer; c. sealing the frontsheet and the rear sheet together along a common peripheral edge to forma volume enclosure having a first volume capacity; d. providing a portsupported by the common peripheral edge and fluidly connected with thevolume enclosure; e. determining whether to expand the volume enclosureto a second volume capacity or leaving the volume enclosure to its firstvolume capacity; f. where volume expansion is desired, expanding thevolume enclosure by introducing a pressurized fluid into the volumeenclosure to permanently stretch at least one of the front or the rearsheets to thereby increase the capacity of the volume enclosure.
 7. Themethod as recited in claim 6 wherein the pressurized fluid is used topermanently stretch both the front and the rear sheets and wherein thepressurized fluid is a gas.
 8. The method as recited in claim 6 whereinthe Step of expanding comprises the steps of: maintaining the rear sheetand the common peripheral edge against a substantially planar surface;and inflating the volume enclosure with a pressurized gas.
 9. The methodas recited in claim 8 wherein the step of maintaining the rear sheet andthe common peripheral edge comprises: providing a multi-piece toolconfigured for receiving the volume enclosure, the tool including alower tool portion and an opposing upper tool portion, the lower toolportion having a lower planer surface and the upper tool portion havingan upper concave surface with a planar edge being configured forcapturing the common peripheral edge against the lower planer surface;and placing the container within the tool wherein the rear sheetcontacts the planar surface of the lower tool portion and the frontsheet faces the concave surface.
 10. The method as recited in claim 9,wherein the step of inflating includes removably coupling pressurizedgas to the port, the gas having an inlet pressure of from about 15 toabout 25 psi, the pressurized gas inflating the volume enclosure withsufficient pressure to stretch the front sheet outwardly against theconcave surface of the tool, wherein the gas is maintained at the inletpressure for a period of about 15 seconds.
 11. The method as recited inclaim 7 wherein the step of expanding comprises the steps of: providinga multi-piece tool configured for receiving the volume enclosure, thetool including a lower tool portion and an opposing upper tool portion,the lower tool portion having a lower concave region with a lower planaredge and the upper tool portion having an upper concave region with anupper planar edge, the lower and upper planer edges being opposed andconfigured for capturing the common peripheral edge; placing thecontainer within the tool wherein the rear sheet faces the upper concaveregion and the front sheet faces the lower concave region; and inflatingthe volume enclosure with a pressurized gas at an inlet pressure of fromabout 15 to about 25 psi to permanently stretch the front and rearsheets outwardly against the respective concave regions of the tool, thegas maintained at the inlet pressure for a period of about 15 seconds.12. The method as recited in claim 11, and further comprising the stepof maintaining the permanently stretched volume enclosure inflated. 13.A method for increasing the capacity of a flexible container for storageand administration, the method comprising the steps of: providing a pairof flexible planar sheets; joining the flexible planar sheets togetherto thereby provide a flexible container having a flexible planar frontsheet opposing a flexible planar rear sheet along a common plane, thefront sheet being sealably attached to the flexible rear sheet along acommon peripheral edge to form a volume enclosure, providing an outletport formed along the common peripheral edge for emptying storedcontents; connecting the common peripheral edge with a peelable seal todivide the volume enclosure into a first volume enclosure and a secondvolume enclosure; expanding at least one of the first or the secondvolume enclosure by introducing a pressurized fluid into the first orthe second volume enclosure to permanently stretch at least one of thefront or rear sheets to thereby increase the capacity of the first orthe second volume enclosure.
 14. The method as recited in claim 13wherein the pressurized fluid is a gas.
 15. The method as recited inclaim 13 wherein the step of expanding comprises the steps of:maintaining the rear sheet and the common peripheral edge substantiallyagainst the common plane; maintaining the peelable seal substantiallyagainst the common plane, and inflating the first or the second volumeenclosure with a pressurized gas to permanently stretch a portion of thefront sheet of the first or second volume enclosure outwardly from thecommon plane.
 16. The method as recited in claim 13 wherein the step ofexpanding comprises inflating the first or the second volume enclosurewith a pressurized gas to permanently stretch both the front and therear sheets of the first or the second volume enclosure.
 17. The methodas recited in claim 13 wherein the stretched volume enclosure supports avolume capacity of at least 1.5 times the original volume.